N-(3-(4 - pyrazolyl) - 3-oxo- or -3-hydroxy-propyl)azacycloaliphatic compounds

ABSTRACT

THE COMPOUNDS OF THE FORMULA   PYR-C(=X)-ALK-CH(R)-N=Z   IN WHICH N=Z DENOTES AN N-AZACYCLOALIPHATIC RESIDUE CONTAINING 5-8 RING MEMBERS AND AT MOST ONE CARBONCARBON DOUBLE BOND, PYR DENOTES A 4-PYRAZOLYL RESIDUE, X STANDS FOR OXYGEN OR A FREE OR SUBSTITUTED HYDROXYL GROUP TOGETHER WITH A HYDROGEN ATOM, ALK REPRESENTS A 1:1-LOWER ALKYLIDENE RESIDUE, AND R DENOTES A HYDROGEN ATOM OR A LOWER ALKYL GROUP, OR SALTS THEREOF HAVE ANTIHYPERTENSIVE , AS WELL AS ANTITUSSIVE OR ANTILNFLAMMATORY PROPERITIES.

United States Patent 3,652,573 N [3-(4 PYRAZOLYL) 3-0X0- 0R -3-HYDROXY-PROPYL1AZACYCLOALIPHATIC COMPOUNDS Vishwa Prakash Arya, Bombay, India,assignor to Ciba Limited, Basel, Switzerland N0 Drawing. Filed Feb. 13,1968, Ser. No. 705,013 Claims priority, application Switzerland, Mar. 1,1967, 2,975/67; Jan. 24, 1968, 1,061/68 Int. Cl. C07d 31/42 US. Cl.260-495 S 5 Claims ABSTRACT OF THE DISCLOSURE The compoundsof theformula in which N=Z denotes an N-azacycloaliphatic residue containing5-8 ring members and at most one carboncarbon double bond, Pyr denotes a4-pyrazolyl residue, X stands for oxygen or a free or substitutedhydroxyl group together with a hydrogen atom, Alk represents a 1:l-lower alkylidene residue, and R denotes a hydrogen atom or a loweralkyl group, or salts thereof have antihypertensive, as well asantitussive or antiinflammatory properties.

SUMMARY OF THE INVENTION The present invention concerns and has for itsobjects the azacycloaliphatic compounds of the Formula A, in which Pyr,X, Alk, R and --N =Z have the above meaning, or salts thereof, processfor their preparation and compositions containing them. The compounds ofFormula A and salts'thereof, as well as compositions containing them areuseful as pharmaceutical, particularly antihypertensive, as well asantitussive, or antiinflammatory agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The N-azacycloaliphatic residue-N=Z is a N-monoa zacycloaliphatic residue and represents primarily asixmembered N-monoazacycloaliphatic residue having at most one doublebond in the ring, such as a piperidino, as well as a 1,4,5,6- orespecially a 1,2,5,6-tetrahydropyridyl residue; it may also denote apyrrolidino, hexahydroazepino or octahydroazocino group. The residue N Zmay optionally contain in the cycloaliphatic portionran oxygen orsulphur atom as ring member, and represent, for example, a 4-morpholinoor 4-thiamorpholino group. The N-azacycloaliphatic residue may beunsubstituted, but preferably contains one, two or more substituents,with onering carbon of the N-azacycloaliphatic residue optionally beingsubstituted by one or two identical or diiferent groups, or one or tworing carbon atoms being substituted by a bivalent substituent. Twonon-adjacent ring carbon atoms may also be connected with each other bya. direct bond, two, preferably non-adjacent, ring-carbon atoms by ahetero, e.g. an oxygen atom. Suitable substituents are, for example,optionally substituted, monovalent or bivalent hydrocarbon residues,heterocyclic residues, acyl residues or free or functionally modifiedcarboxyl groups, as well as free or functionally converted hydroxyl orfree or substituted amino groups.

Hydrocarbon residues which should be quoted are aliphatic'hydrocarbonresidues, preferably having at most 7 carbon atoms,forexample, lower alkyl, e.g. methyl or ethyl, linear or branchedpropyl, bntyl or pentyl, bonded at any desired position, lower alkenyl,e.g. allyl or methallyl, or lower alkinyl, e.g. propargyl, as well ascycloaliphatic hydrocarbon residues, preferably having 3-8 ring carbonatoms, such as cycloalkyl, e.g. cyclopentyl or cy- 3,652,573 PatentedMar. 28, 1972 clohexyl, or alicyclicaliphatic hydrocarbon residues,preferably having 3-8 ring carbon atoms and at most 7 chain carbonatoms, such as cycloalkylalkyl, e.g. cyclopentylmethyl, cyclohexylmethylor cyclohexylethyl, aromatic hydrocarbon residues, particularlymonocyclic or bicyclic residues of this type, e.g. pheny lor naphthyl,or araliphatic hydrocarbon radicals, such as phenyl-lower alkyl ornaphthyl-lower alkyl, e.g. benzyl, phenylethyl, diphenylmethyl ornaphthylmethyl. Bivalent hydrocarbon residues are especially those ofaliphatic type, such as lower alkylene group having at most 7 carbonatoms, e.g. methylene, 1,2-ethylene, 2,2-propylene, 1,3-propylene,1,4-butylene or 1,5-pentylene radicals, in which the chain carbon atomsmay optionally be replaced by hetero-atoms e.g. nitrogen or oxygenatoms.

These hydrocarbon residues may optionally be mono-, diorpoly-substituted. Thus, for example, aliphatic hydrocarbon residuescontain as substituents free or substituted hydroxyl or mercapto groups,such as etherified hydroxyl or mercapto groups having preferably up to 7carbon atoms, for example, lower alkoxy, e.g. methoxy or ethoxy, orlower alkylmercapto, e.g. methylmercapto or ethylmercapto, or esterifiedhydroxyl groups, preferably having up to 7 carbon atoms, for example,lower alkanoyloxy, e.g. acetyloxy, or reactive esterified hydroxygroups, such as sulfonyloxy groups, e.g. phenylsulfonyloxy groups, orhalogeno, e.g. fluoro, chloro or bromo, or acyl, preferably having up to7 carbon atoms, such as lower alkanoyl, e.g. acetyl or propionyl, orcarbo-lower alkoxy, e.g. carbethoxy, or free or substituted amino,primarily monoor di-lower alkylamino, e.g. methylamino, dimethylamino,ethylamino or diethylamino, or alkyleneamino, oxaal kyleneamino orazaalkyleneamino, having up to 8 ring members, e.g. pyrrolidino,piperidino, morpholino, piperazino, 4-lower alkylpiperazino, forexample, 4-methyl-piperazino, or 4-hydroxy-lower alkyl-piperazino, forexample, 4-(2-hydroxyethyl)-piperazino, in which one substituent of thenitrogen atom may also be bonded to the aliphatic hydrocarbon residue,as in l-lower alkyl-4- piperidyl, e.g. l-methyl-piperidyl, or as inl-lower alkyl- 3-pyrrolidyl-lower alkyl, e.g.1-methyl-3-pyrrolidylmethyl. substituents of cycloaliphatic hydrocarbonresidues are primarily lower alkyl, preferably having up to 7 carbonatoms, whereas aromatic residues may contain as substituents theabove-mentioned substituents, primarily lower alkyl, lower alkoxy, loweralkylmercapto, lower alkanoyloxy, halogeno, trifluoromethyl, carbo-loweralkoxy, lower alkanoyl or free or substituted amino, as well as nitro orlower alkylenedioxy, e.g. methylenedioxy.

The heterocyclic substitutents of the azacycloaliphatic group areespecially monocyclic, as Well as bicyclic heterocyclic residues havingaromatic properties, primarily monocyclic azacyclic, as well asoxacyclic or thiacyclic residues of this type, for example, pyridyl,e.g. 2-, 3- or 4-pyridyl, as well as furyl, e.g. Z-furyl, or thienyl,e.g.

2-thienyl, but also bicyclic heterocyclic residues, preferablybenzoazacyclic residues of aromatic character, in which the azacyclicring contains 5-6 ring members and up to three nitrogen atoms or one ortwo nitrogen atoms together with an oxygen or a sulphur atom as ringmembers, as, for example, the bicyclic heterocyclic groups describedbelow which may substitute the l-position of the 4-pyrazolyl residue.The heterocyclic residues may optionally contain the above-mentionedsubstituents of a hydrocarbon residue and may, in particular, besubstituted like the above-mentioned aromatic residues and/or linked tothe N-azacycloaliphatic residue via an aliphatic hydrocarbon radical,such as a lower alkylene radical.

An acyl residue optionally substituting the N-azacycloaliphatic residuemay, for example, denote the residue of an aliphatic carboxylic acid,especially a lower alkanecarboxylic acid, which preferably contains upto 7 carbon atoms, e.g. acetic, propionic, n-butyric, isobutyric orpivalic acid, as well as the acyl residue of a cycloaliphatic carboxylicacid, which preferably contains 3-8 ring carbon atoms, such as acycloalkane carboxylic acid, e.g. cyclopentanecarboxylic orcyclohexanecarboxylic acid, or a cycloaliphatic-aliphatic carboxylicacid, which preferably contains 3-8 ring carbon atoms and up to 7 chaincarbon atoms, such as a cycloalkyl-lower alkanecarboxylic acid, e.g.cyclopentylpropionic or cyclohexylacetic acid, or the acyl group of anaromatic carboxylic acid, preferably a monocyclic or bicyclic aromaticcarboxylic acid, e.g. benzroic acid, an araliphatic, preferably amonocyclic or bicyclic, araliphatic carboxylic acid, such asphenyl-lower alkane carboxylic, e.g. phenylacetic acid, or aheterocyclic, especially a monocyclic, azacyclic, oxacyclic orthiacyclic, carboxylic acid or aromatic character, e.g. nicotinic orisonicotinic acid. The acyl residue of such organic carboxylic acids mayoptionally contain the above-mentioned substituents, such as those ofthe previously mentioned hydrocarbon residues.

Functionally modified carboxyl groups which may occur as substituents ofthe azacycloaliphatic residue apart from free carboxyl groups, areprimarily esterified carboxyl groups, such as carbo-lower alkoxy, e.g.carbomethoxy, carbethoxy, carbo-n-propyloxy or carbo-n-butyloxy, as wellas nitrogen-containing functionally converted carboxyl groups, such asoptionally N-substituted carbamyl, e.g. carbamyl or N-lower alkylcarbamyl, such as N-methyl-carbamyl, N,N dimethyl carbamyl,N-ethylcarbamyl, or N,N-dicthyl-carbamyl, or cyano.

Free or functionally converted hydroxyl groups are also possiblesubstituents of the N-azacycloaliphatic residue; the latter are, forexample, etherified hydroxyl groups, such as lower alkoxy or loweralkenyloxy having preferably up to 7 carbon atoms, e.g. methoxy, ethoxy,n-propyloxy, isopropyloxy or allyloxy, or esterified hydroxyl groups,such as carbamoyloxy, N-lower alkylcarbamoyloxy, N,N-di-loweralkylcarbamoyloxy, lower alkoxy-carbonyloxy or lower alikanoyloxy, inwhich the carbamyl, carbo-lower alkoxy and lower alkanoyl residues havethe significance given above, or halogeno, e.g. fiuoro, chloro or bromo,as well as organic sulphonyloxy groups, e.g. p-toluenesulphonyloxy ormethylsulphonyloxy.

The amino substitutents of the N-azacycloaliphatic residue are primary,secondary or tertiary amino groups, such as amino, lower alkylamino,e.g. methylamino or ethylamino, di-lower alkylamino, e.g. dimethylaminoor diethylamino, or especially alkyleneamino, preferably having 4-8 ringmembers, e.g. pyrrolidino or piperidino, azalkyleneamino, preferablyhaving 6-8 ring members, such as piperazino group, e.g.4-methyl-piperazino, or oxaalkyleneamino, preferably having 6 ringmembers, e.g. morpholino.

The N-azacycloaliphatic residue N=Z primarily represents one of theresidues of formulae Rb u in which n denotes -7, R represents a hydrogenatom or an optionally substituted hydrocarbon residue, particularly anoptionally substituted aromatic hydrocarbon residue, as Well as anoptionally substituted heterocyclic residue of aromatic character, R (inthe saturated grouping) represents a hydrogen atom or a free orpreferably functionally modified carboxyl group, as well as an acylgroup, a free or functionally converted hydroxyl or a free orsubstituted amino group, and R, (in the unsaturated grouping having onecarbon-to-carbon double bond in the ring) denotes hydrogen, or R and Ras well as R, and R together denote a lower alkylene group.

A 4-pyrazolyl residue may be unsubstituted in the l-position, butpreferably contains a substituent in this position, primarily anoptionally substituted hydrocarbon residue, a heterocyclic residue ofaromatic character or an acyl residue. The hydrocarbon residues andheterocyclic residues are primarily the above-mentioned residues whichsubstitute the N-azacycloaliphatic grouping -N=Z, such as optionallysubstituted aliphatic hydrocarbon residues, for example, lower alkyl,lower alkenyl or lower alkinyl, optionally substituted cycloaliphatichydrocarbon residues, for example, cycloalkyl, optionally substitutedcycloaliphatic-aliphatic hydrocarbon residues, for example,cycloalkyl-lower alkyl, optionally substituted aromatic hydrocarbonresidues, especially monocyclic or bicyclic aromatic residues, oroptionally substituted araliphatic, especially monocyclic or bicyclicaraliphatic hydrocarbon residues. Heterocyclic residues areprimarilymonocyclic or bicyclic heterocyclic residues having aromaticproperties, bicyclic heterocyclic residues preferably beingbenzoazacyclic residues of aromatic character in which the azacyclicring contains 5-6 ring members and up to 3 nitrogen atoms or 1 or 2nitrogen atoms together with 1 oxygen or 1 sulphur atom as ring members,primarily quinolyl, e.g. 2-, 3-, 4- or 8-quin0lyl, isoquinolyl, e.g.l-isoquinolyl, cinuolinyl, e.g. 3- or 4-cinnolinyl, quinazolin'yl, e.g.2- or 4-quinazolinyl, quinoxalinyl, e.g. 2-quinoxalinyl, phthalazinyl,e.g. l-phthalazinyl, benzotriazinyl, e.g. 1,2,3- or1,2,4-benzotriazinyl, benzothiadiazinyl, e.g.1,1-dioxo-2H-1,2,3-benzothiadiaZin-4-yl, benzimidazolyl, e.g. l-loweralkyl 2-benzimidazolyl, benzoxazolyl, e.g. Z-benzoxazolyl,benzisoxazolyl, e.g. 3-benzisoxazolyl, benzothiazolyl, e.g.2-benzothiazolyl, or benzisothiazolyl, e.g. 3-benzisothiazolyl groups.These residues may optionally contain the above-mentioned substituents,the bicyclic heterocyclic residues of aromatic character may besubstituted, for example, in the same manner as the above-mentionedaromatic residues substituting the N-azacycloaliphatic residue.

An acyl group substituting the l-position of the 4-pyrazolyl residue isprimarily the acyl residue of an organic carboxylic acid, especially ofa functionally modified carbonic acid which is, for example, representedby a functionally modified carboxyl group, preferably the acyl residueof a monoester of carbonic acid, which, is for example, represented by acarbo-lower alkox'y group, or the acyl residue of a carbonic acidmonoamide, which is, for example, represented by an optionallyN-substituted carbamyl group, as well as the acyl residue of analiphatic carboxylic acid, especially a lower alkanecarboxylic acid, aswell as of a cycloaliphatic, aromatic or araliphatic carboxylic acid, orof a heterocyclic carboxylic acid of aromatic character, such as, forexample, the acyl residues referred to above, which may optionally besubstituted, for example, as the hydrocarbon residues substituting theN-azacycloaliphatic residue.

The new compound may furthermore contain other substituents in thepyrazole ring, especially lower alkyl, phenyl or pyridyl groups, thesegroups being optionally substituted as referred to above. The pyrazolenucleus preferably contains in 5-position a lower alkyl group, forexample,

one of the above-mentioned residues, especially a methyl group, whichmay optionally be substituted by an etherified hydroxy group, such as alower alkoxy, e.g. methoxy or ethoxy.

A hydroxyl group X is advantageously a free hydroxyl group; it may,however also be substituted and may, for example, represent afunctionally converted, particularly an etherified hydroxyl group, suchas a hydroxyl group substituted by a lower aliphatic hydrocarbonresidue, for example, a lower alkyl or lower alkenyl group havingpreferably up to 7 carbon atoms, e.g. methyl, ethyl, propyl, isoprop'ylor allyl. Substituted hydroxy may also be an esterified hydroxyl group,for example, esterified by an amide, N-lower alkylamide or anN,N-di-lower alkylamide or a lower alkyl ester of carbonic acid or by alower alkanecarboxylic acid, such as, for example, one of theabove-mentioned acids.

The residue Alk is a 1,1-lower alkylidene radical, for

example, a 1,1-ethylidene radical or a,1,l-propy1idene radical, butabove all a methylene radical. The group R primarily represents ahydrogen atom, but may also represent lower alkyl, preferably having upto 7 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl or tert.-butyl.

The new compounds exhibit valuable pharmacological properties. Apartfrom psychotropic effects, they primarily show antihypertensiveproerties, which are demonstrable in test animals, such as cats, dogs orrats. Furthermore, the compounds show central nervous systemsdepressants, e.g. tranquillizing, sedative and anticonvulsiveproperties, as well as antitussive, antiinflammatory, adrenolytic orbarbiturate-potentiating effects. The new compounds are, therefore,useful as pharmacologically effective compounds, primarily asanti-hypertensive compounds. Thus, on the basis'of animal tests, it hasbeen found, that the compounds show antihypertensive effects at a dosageof about 0.00025 g./kg. to about 0.01 g./kg. (in rats, when given orallyor intravenously). n the basis of other animal tests, compounds of thepresent invention show antitussive properties in cats at doses of about0.002 g./ kg. to about 0.01 g./kg. (intravenous application), andantiinfiammatory effects in rats at doses of about 0.03 g./ kg. to about0.1 g./kg. (oral application). They are also useful as intermediates inthe preparation of other valuable compounds, especially ofpharmacologically active substances.

Compounds having particularly valauble pharmacological, especiallyantihypertensive properties are those of formulae R denotes a loweralkyl residue, optionally substituted by a free or functionallyconverted, particularly reactive esterified hydroxy or free orsubstituted amino, a phenyl residue, optionally substituted by 1, 2 ormore halogeno, trifiuor'ornethyl, lower alkyl, lower alkoxy, amino and/or nitro, a phenyl-lower alkyl residue optionally substituted like thephenyl residue, a pyridyl residue optionally substitutedas the phenylresidue, a bicyclic benzoazacyclic residue of aromatic character,optionally substituted like the phenyl residue, in which the azacyclicring contains -6 ring members and up to 2 nitrogen atoms or a nitrogenatom togetherwith an oxygen atom or a sulfur atom as ring members, orthe acyl residue of a mono-functionally modified, particularlymono-esterified carbonic acid, or of 'a lower alkanecarboxylic acid, Rdenotes lower alkyl, as well as lower alkoxy-lower alkyl, R denotes ahydrogen atom or lower alkyl, R; stands for a hydrogen atom or loweralkyl, and the residue N=Z denotes the saturated group of the formula vor the unsaturated group of the formula r m ln nh n which contains acarbon-carbon double bond in the ring, in which formulae n denotes 5 or6, R represents hydrogen or phenyl optionally substituted like thephenyl residue R R denotes hydrogen, a functionally modified carboxylgroup, a free, esterified or etherified hydroxyl group, or a di-loweralkylamino, a 5-8 ring-membered alkylenamino, a morpholino or a 4 loweralkyl-piperazino group, and R1 represents hydrogen atom, or R -and R aswell as R and R when taken together, denote a lower alkylene group.

In the compounds of Formulae I and II, R, preferably denotes a free orfunctionally converted, particularly reactive esterified B- or-hydroxy-lower alkyl group, a 6- or 'y-amino-lower alkyl group, whereinthe amino group may be unsubstituted or substituted by one or two loweralkyl groups or by a lower alkylene residue having 47 carbon atomsoptionally interrupted by an oxygen or sulphur atom or by an optionallysubstituted, for example, lower alkyl-substituted nitrogen atom group, aphenyl residue which may optionally contain 1, 2 or more fluorine,chlorine or bromine atoms, methyl, methoxy, trifiuoromethyl, amino and/or nitro groups, a phenyl-lower alkyl group which may optionally besubstituted in the phenyl nucleus like the phenyl residue, a pyridylgroup which may optionally be substituted like the phenyl residue, abicyclic benzoazacyclic group of aromatic character, which mayoptionally be substituted like the phenyl residue and in which theazacyclic ring contains 5 ring members and 1 nitrogen atom together withan oxygen atom or a sulphur atom as ring members, or 6 ring members andup to 2 nitrogen atoms as ring members, or a carbo-lower alkoxy or alower alkanoyl group, R denotes a methyl, as well as a methoxymethylgroup, R is hydrogen, and R stands for hydrogen or lower alkyl, e.g.methyl or ethyl, and wherein the residue -N==Z denotes the group offormula or the group of formula O H Rail on-onz-orrrN l C R .R2/

and

in which R represents fl-hydroxyethyl or fl-halogenoethyl, e.g. aB-chloroethyl, or a fi-sulfonyloxyethyl group, such as aB-phenylsulfonyloxyethyl group optionally substituted in the phenylportion by one, two or more halogeno, lower alkyl, lower alkoxy,trifiuoromethyl, amino or nitro, e.g. fl-phenyl sulfonyloxyethyl,fl-4-methylphenylsulfonyloxyethyl or -4-bromophenylsulfonyloxyethyl, aswell as fl-4-chlorophenylsulfonyloxyethyl, or a ,8- or 'yamino-loweralkyl group, wherein the amino group is unsubstituted or monoordisubstituted by lower alkyl or lower alkylene, the latter having 4-6chain carbon atoms which may optionally be interrupted by an oxygen atomor an optionally N-lower alkyl substituted nitrogen atom, such as,G-aminoethyl, ,8-N,N di-lower alkyl-aminoethyl, afl-N,N-alkyleneaminoethyl, in which alkylene has 4-6 chain carbon atoms,,B-morpholino-ethyl, B-piperazinyl ethyl or fi-4-loweralkyl-piperazinyl-ethyl, phenyl optionally substituted as shown above,phenyl-lower alkyl, e.g. benzyl or phenylethyl optionally substituted inthe phenyl nucleus like the above phenyl residue, :1 pyridyl,benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl,phthalazinyl or quinoxalinyl residue optionally substituted like theabove phenyl residue, or carbo-lower alkoxy, R stands for methyl, aswell as methoxymethyl, R denotes phenyl optionally substituted like thephenyl residue R and R, has the previously given meaning.

In the above-mentioned Formulae Ia, IIa, lb and LIbR, primarily denotesfl-hydroxyethyl or, phenyl optionally substituted by one, two or morefiuoro, chloro, bromo, methyl, trifluoromethyl, methoxy, amino and/ornitro groups, as well as benzyl or phenylethyl optionally substituted inthe phenyl nucleus like the phenyl residue or pyridyl, optionallysubstituted as the phenyl nucleus, and also Z-benzothiazolyl,Z-quinolinyl, 4-quinolinyl, l-isoquinolinyl, 3-cinnolinyl, 4-cinnolinyl,2-quinazolinyl, 4- quinazolinyl, l-phthalazinyl or Z-quinoxalinyl, thesere'sidues being optionally substituted as the phenyl residue, with2-quinoxalinyl and 3-methyl-2-quinoxalinyl being particularly preferredfrom amongst the bicyclic azacyclic substituents of aromatic character,or carbo-lower alkoxy, e.g. carbomethoxy or carboxy, R stands formethyl, as well as methoxymethyl, R denotes phenyl optionallysubstituted like the phenyl residue R and R denotes cyano, carbo-loweralkoxy, e.g. carbomethoxy, carboethoxy, lower alkanoyloxy, lower alkoxyor hydrogen.

iParticularly pronounced pharmacological, especially antihypertensive,properties are shown by the 4-{3-[4-(4-fluorophenyl)-1,2,5,6-tetrahydro-l-pyridyl] 1oxo-propyl}-l-(2-hydroxyethyl)-5-methyl-pyrazole, the 1-(3-fluorophenyl)4-{3-[4-(4-fiuorophenyl) l,2,5,6tetrahydro-l-pyridyl]-l-oxopropyl}-5-methyl-pyrazole, and the 1-(2-hydroxyethyl) 5methyl-4[3-(4-phenyl-l,2,5,6-tetrahydro-l-pyridyl)-l-oxo-propyl]-pyrazole,as well as the 1-(2-hydroxyethyl)-5-methyl-4-{3-[4(3-trifluoromethylphenyl) 1,2,5,6 tetrahydro-l-pyridyl]-1-oxo-propyl}-pyrazole and the S-methoxymethyl-l-phenyl-4-[3-(4-phenyl-1,2,5,6tetrahydro 1 pyridyl)-3-oxo-propyl]-pyrazole and the salts, such as theacid addiiton salts, particularly the non-toxic acid additional saltsthereof, which, when given to experimental animals, such as rats, indoses of about 0.00025 g./kg. to about 0.01 g./kg., (intravenous or oralapplication), produce outstanding antihypertensive effects.

Antitussive properties are shown by 1-carbethoxy-4-[3-(4-carbethoxy-4-phenyl-piperidino) l oxo-propyl]- S-methylpyrazoleand the l-(2-fluorophenyl)-4-{3-[4-(4- fluorophenyl) 1,2,5,6tetrahydro-l-pyridyl]-l-oxo-propyl}-5-methyl-pyrazole and their salts,such as the acid addition salts, particularly the non-toxic acidaddition salts, which when given to experimental animals, such as catsat doses of about 0.002 g./kg. to about 0.01 g./kg. (intravenousapplication) produce significant antitussive effects.

Anti-inflammatory effects are exhibited by the1-(4-fiuorophenyl)-4-{3[4-(4-fiuorophenyl) l,2,5,6-tetrahydro-1-pyridyl]-1-oxo-propyl}-S-methyl-pyrazole and the l-(2-fluorophenyl)-4-{3-[4-(4-fluorophenyl) 1,2,5,6tetrahydro-l-pyridyl]-l-oXo-propyl}-5-methylpyrazole and their salts,such as the acid addition salts, particularly the nontoxic acid additionsalts, which when given to experimental animals, such as rats at dosesof about 0.03 to about 0.1 g./kg. (oral application) produce significantanti-inflammatory activity.

The new compounds are obtained by methods which are in themselves known,for example, by (a) reacting a compound of formula PyrC(:O)AlkH with alower alkanal and an azacycloaliphatic compound of formula HN=Z or anamine compound having at least one hydrogen atom attached to thenitrogen and permitting the formation of an N-azacycloaliphatic residueof formula --N=Z, and forming the N-azacycloaliphatic group of theformula -N=Z, and in a resulting compound having a group permitting theformation of the N-azacycloaliphatic group of the formula N=Z, or (b)reacting a compound of formula or PyrC(=X)-Alk'=CH(R), in which Y is aneliminable group, and Alk' denotes a 1,1,1-lower alkylidyne group, withthe said azacycloaliphatic compound or amine compound and forming theN-azacycloaliphatic resiidue N=Z in a resulting compound having a grouppermitting the formation of the N-azacycloaliphatic residue -N=Z, or (c)reductively replacing in a compound of the formula Pyr-C(=X)AlkCH(R)N=Z,in which at least one of the methylene groups adjacent to the nitrogenatom of the azacycloaliphatic ring carries an 0x0 or thiono group, suchgroup by two hydrogen atoms, or (d) reacting a compound of the formula(acyl-formylmethyl)C(=X)AlkCH(R)-N=Z, in which acyl represents theresidue of an organic carboxylic acid or an enol or enol derivativethereof with a compound of the formula R -NHNH or (e) reducing in acompound of the formula the olefinic double bond, and if desired orrequired, re ducing at any stage of the process an oxo group X into ahydroxyl group and/or substituting a hydroxyl group or oxidizing it toan oxo group, and/ or, if desired, converting at any stage of theprocedure an azacycloaliphatic residue into another azacycloaliphaticresidue, and/or, if desired, in a resulting compound converting asubstituent into another and/or eliminating a substituentand/orintroducing a substituent, and/or, if desired, converting-a resultingfree base into a salt or a resulting salt into the free base or intoanother salt, and/or, if desired, resolving a mixture of isomers intoits constituent isomers.

The reaction of a compound of formula PyrC(=O)AlkH with a lower alkanal,especially with formaldehyde, and with the azacycloalphatic compoundHN:Z or the amine compound is carried out in accordance with the Mannichreaction. Instead of the lower alkanal, it is also possible to usereagents capable of releasing the latter, such as functionalderivatives, for example, acetals or acylates, or their polymerisationproducts, optionally with the addition of acid. Thus, for example,formaldehyde may be used in the form of paraformaldehyde ortrioxymethylene. The azacycloaliphatic compound or the amino compound ispreferably used in the form of a salt. The reaction preferably takesplace in the presence of a diluent, e.g. an alcohol or dioxane, or asolvent mixture or an aqueous mixture; when polymerisation products ofthe aldehyde are used, it is advisable to work in an organic diluent,such as one of those mentioned above, or also in benzene, toluene,nitrobenzene or nitromethane. Usually, the reaction is carried out atelevated temperatures; one may also work in a closed vessel.

The reaction of the compound of the formula in which the eliminablegroup Y is preferably a reactive esterified hydroxyl group, primarily ahalogen atom or a sulphonyloxy group, such as a benzenesulfonyloxygroup, e.g. p-toluenesulfonyloxy, as well as a suitable carbonyloxygroup, e.g. acetyloxy or ethoxycarbonyloxy, but may also be aN-unsubstituted or N-polysubstituted amino group (in which case thestarting material is preferably used in the form of a salt), and Xprimarily denotes the oxo group, or of the corresponding unsaturatedcompound of the formula Pyr--C (=X)Alk=CHR, which may be formed in situfrom the above compounds of the formula Pyr-C(=X)-AlkCH(R)-Y, with theazacycloaliphatic compound of formula H-N=Z or the amine compound iscarried out in the usual manner; starting materials having a reactiveesterified hydroxyl group are preferably reacted in the presence of anacid-binding material, such as a basic condensation agent.

As amine compounds permitting the formation of an N-azacycloaliphaticresidue, one may use ammonia or above all primary amines, thesubstituents of which permit ring closure with the formation of theN-azacycloaliphatic residue. Such residues are, for example, aliphaticresidues carrying a free or reactive esterified hydroxyl or an aminogroup.

The synthesis of the N-azacycloaliphatic residue takes place in theusual manner. Thus, a compound with a free amino group may be reactedwith a reactive diester of an appropriate 4-7-membered aliphatic diol tofurnish the azacycloaliphatic ring directly. It is however alsopossible, by starting with compounds having the free amino group, tocarry out a substitution with reactive derivatives of 4-7-memberedaliphatic diols or aminoalcohols, to obtain secondary amines, whichcarry at the amine group the substituents needed for the formation ofthe azacycloaliphatic ring. In resulting secondary amines, an aliphaticresidue which contains, for example, a free or reactive esterifiedhydroxyl group or amino group, the hydroxyl group may, if desired, befirst reactively esterified, for example, by means of halides of sulphuror phosphorus, especially thionyl chloride, or by means of organicsulphonyl halides, e.g. p-toluenesulphonyl chloride, and the ringclosure to furnish the azacycloaliphatic ring may then be carried out,for example, by eliminating water or, preferably, an acid, as well asammonia, where necessary, in the presence of a condensing reagent.

The reductive replacement of an oxo or thiono group by two hydrogenatoms follows the usual practice. A carbonyl group is converted into amethylene group, for example, by treating the starting material with asuitable light metal hydride, e.g. lithium aluminium hydride, ifnecessary, in the presence of an activator, such as aluminium chloride,or with hydrogen in the presence of a suitable catalyst, e.g. acopper-chromium catalyst, a thiocarbonyl group, for example, bytreatment with a hydrogenating catalyst, e.g. Raney nickel, in thepresence of a suitable solvent, e.g. an alkanol, and, if necessary, ofhydrogen. During this reaction, simultaneously reducible substituents,for example, an oxo group X, may be reduced as well and, for instance,be converted into a hydroxyl group.

The reaction of a compound of formula R NH-NH as in modification (d) ispreferably carried out with a suitable enol derivative, particularly alower alkyl, e.g. methyl or ethyl enol ether, of a compound of theformula Ntacyl-formylmethyl)C(=X)-Alk-CH(R)-N=Z;

10 one may proceed stepwise, for example, a hydrazono intermediate maybe formed which may then be ring closed, for example, by heating, intothe desired product.

An olefinic bond in a starting material of the formulaPyr--C(=X)Alk'=C(R)N=Z may be saturated, for example, by catalytichydrogenation, e.g. treatment with hydrogen in the presence of a noblemetal catalyst, such as a palladium catalyst, if necessary, underpressure. Simultaneously, other reducible groups in the molecule, suchas an oxo group, may be reduced.

The reduction of an oxo group X to a hydroxyl group is carried out inthe usual manner. The group is preferably reduced by, for example,treatment with nascent hydrogen, such as with a metal in the presence ofa hydrogen-releasing agent, for example, with sodium in an alcohol, orby treatment with a complex metal hydride, e.g. sodium borohydride, orwith hydrogen in the presence of a hydrogenation catalyst, for example,a platinum, palladium, rhodium, nickel or copper catalyst, such asplatinum oxide, palladium black, Raney nickel or copper chromite orrhodium on a carrier, such as aluminum oxide or charcoal. The reductionpreferably takes place in the presence of diluents and/or solvents,under cooling, at normal temperature or while heating, in open vesselsor in closed vessels under pressure. The reduction of the 0x0 group mayalso take place according to the Meerwein-Ponndorf- Verley method, forexample, in the usual manner by treatment with a lower alkanol, such asisopropanol, in the presence of an appropriate alcoholate, e.g.aluminium isopropylate.

In resulting compounds having free hydroxyl groups, the latter may besubstituted in the usual manner. Etherification may, for example, becarried out by treatment with a diazo-compound, such as a diazo-loweralkane, e.g. diazomethane or diazoethane, optionally in the presence ofa suitable Lewis acid, e.g. fluoboric acid, aluminium chloride, borntrifluoride etherate or aluminium lower alkanolate. It is however, alsopOSSible to form a metal salt and react the latter with a reactive esterof an alcohol, or the hydroxyl group may be reactively esterified, forexample, by replacing it by a halogen atom or converting it to anorganic sulphonyloxy group, and can then be reacted with an alcohol,preferably in the form of a metal compound. The esterificationpreferably takes place by treatment with acid halides, acid anhydridesor ketenes, isocyanates or isothiocyanates, where appropriate in thepresence of a condensing agent, such as a base capable of combining withacids.

If desired, a hydroxyl group may be converted into an oxo group X inknown manner with a suitable oxidation reagent such as, for example, achromium-V'l-compound.

The conversion of one N-azacycloaliphatic residue to another may takeplace by methods which are in themselves known. Thus, it is, forexample, possible to eliminate, for example, in the form of water or anacid, from a saturated N-azacycloaliphatic residue a removable residue,such as a free or esterified hydroxyl group, e.g. a halogen atom or asulphonyloxy group, together with a hydrogen atom, and thus to introducea carbon-carbon double bond into the N-azacycloaliphatic ring. Theelimination of water or acids may be, for example, carried out withwarming and/or in the presence of suitable reagents, such as acids, e.g.p-toluenesulphonic acid, or of bases, for example, sodium hydroxide.

In N-azacycloaliphatic residues having a carbon-carbon double bond, thelatter may be saturated by reduction, for example, by treatment withcatalytically activated hydrogen.

Furthermore, substituents in resulting compounds may be converted intoother substituents. Thus, the conversion of a hydroxyl group present inthe substituent attached to the 1-position of the pyrazole nucleus to anesterified hydroxy group is carried out in a known manner, for example,as described before. Reactive esterified hydroxyl groups are convertedto amino groupings by reaction with 11 the appropriate amino compounds,either directly or in the presence of a suitable diluent, if necessary,while heat- Free carboxyl groups may be converted in a manner which isin itself known into functionally converted carboxyl groups, forexample, by esterification (eg. treatment with a diazo compound or withan alcohol in presence of a suitable esterification reagent, such asdicyclohexylcarbodiimide, or conversion of the carboxyl group to ahalogenocarbonyl group and reaction with an alcohol or a metal compoundthereof), or by amidation (e.g. by treatment with ammonia or an amine inthe presence of a suitable condensation reagent, such adicyclohexylcarbodiimide, or by conversion of the carboxyl group to thehalogenocarbonyl group and reaction thereof with ammonia or an amine).

Functionally modified carboxyl groups, such as esterified or amidatedcarboxyl groups, as well as cyano groups, may, for example, be convertedto the free carboxyl group by saponification with acid or basicreagents, or may, for example, be converted to esterified carboxylgroups by alcoholysis; these reactions are carried out in a manner whichis in itself known.

Furthermore, nitro groups may subsequently be reduced in the usualmanner, for example, by treatment with catalytically activated hydrogen,or nascent hydrogen; this reduction may take place simultaneously with areduction of an oxo group X to the hydroxyl group.

Substituents may be eliminated in a manner which is in istelf known;free carboxyl groups may, for example, be eliminated by decarboxylationat elevated temperatures, and cx-aphenylalkyl groups, e.g. benzylgroups, which substitute a nitrogen or oxygen atom may, for example, beeliminated by hydrogenolysis in the presence of a suitable hydrogencatalyst.

Substituents may be introduced into resulting compounds according to perse known methods. Thus, for example, the hydrogen atom of a pyrazolenucleus unsubstituted in l-position, may be replaced by a substituent,for example, by treatment with a compound containing a reactiveesterified hydroxyl group, such as an aliphatic halogen compound or anacid halide, or an aryne or diazonium compound, if necessary, after theformation of a derivative, such as a metal, preferably an alkali metal,e.g. sodium, compound, or in the presence of a condensation agent.

The above reactions are carried out in the usual manner, while cooling,at normal temperature, or while heating, in an open or closed vessel, ifnecessary, under pressure, in the presence or absence of diluents and/orcatalysts and/or condensation agents, and/or in an inert gas atmosphere.

Depending on the reaction conditions the new compounds are obtained infree form or in the form of their salts.

The salts of compounds of the present invention are acid addition salts,for example, non-toxic, pharmaceutically useful acid addition salts,primarily those of inorganic acids, e.g. hydrochloric, hydrobromic,nitric, sulfuric or phosphoric acid, as well as of organic acids, suchas organic carboxylic acids, e.g. acetic, propionic, glycollic, malonic,suceinic, maleic, hydroxymaleic, fumaric, malic, tartaric, citric,benzoic, cinnamic, mandelic, salicylic, 4 aminosalicylic, 2phenoxy-benzoic, 2- acetoxy-benzoic, embonic, nicotinic or isonicotinicacid, or of organic sulfonic acids, e.g. methanesulphonic,ethanesulphonic, Z-hydroxyethanesulphonic, ethane-1,2- disulphonic,benzenesulphonic, p-toluenesulphonic, naphthalene 2 sulphonic orcyclohexylsulfamic acid. Salts of such acids, as well as other acidaddition salts, may furthermore be used as intermediate products, forexample, for purifying the free compounds, or for the preparation ofother salts, as well as for identification purposes. Salts which areespecially suited for identification purposes are, for example, those ofpicric, picrolonic, fiavianic, phos- 12 photungstic, phosphomolybdic,chloroplatinic, Reinecke or perchloric acid.

The resulting salts may be converted to the free bases in a manner whichis in itself known, for example, by treatment with a base such as ametal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassiumhydroxide or calcium hydroxide, a metal carbonate, e.g. sodium,potassium or calcium carbonate or hydrogen carbonate, or with ammonia ora suitable hydroxyl ion exchanger.

The resulting salts may be converted to other salts in a manner which isin itself known, for example, by treating a salt of an inorganic acidwith a suitable metal salt, e.g. sodium, barium or silver salt of anacid, in a suitable solvent in which the resulting inorganic salt isinsoluble and is, therefore, removed from the reaction medium, or bytreatment with an ion exchanger.

The resulting free bases may be converted to their acid addition saltsin a manner which is in itself known, for example, by treating thesolution of a base in a suitable inert solvent or solvent mixture withan acid, such as one of the above mentioned ones, or with a solutionthereof, or with a suitable anion exchanger. The salts may also beobtained in form of their hydrates or may include the solvent used forcrystallisation. Because of the close relationship between the newcompounds in free form and in the form of their salts, the freecompounds or the salts are in the present context, also to be understoodas the corresponding salts and free compounds, respectively, whereversuch as appropriate and feasible.

Resulting isomer mixtures may be separated into the individual isomersin a manner which is in itself known. Racemates may be resolved into theoptically active dand l-forms, for example, by crystallisation fromoptically active solvents or by treatment of the racemic com pound,preferably in the presence of a suitable solvent, with one of theoptically active forms of an acid having asymmetric carbon atoms, andisolation of the diastereoisomeric salts.

The invention also relates to those modifications of the method,according to which one starts from the compound obtainable as anintermediate at any stage of the procedure and carries out the remainingprocess stages, or interrupts the procedure, or in which a startingmaterial is formed under the reaction conditions or used in the form ofa derivative, e.g. a salt thereof.

In the method of the present invention one preferably uses such startingmaterials as lead to the compounds which were initially described asbeing particularly valuable.

The starting substances used in this invention are known or may beobtained by known methods. Thus, compounds of the formula PyrC(=O)-AlkHare obtained, for example, by treating suitably substitutedu,'y-diketones, such as fl-hydroxy-methylene-a,'y-dione compounds orderivatives thereof, e.g. ethoxymethylene-acetylacetone, with hydrazinesand ring closing the resulting hydrazones, for example, by heating. Inthe starting materials so produced it is, for example, possible tointroduce a hydroxymethyl group into the sidechain by treatment withformaldehyde, and either to eliminate a hydroxyl group from a resultingcompound together with a hydrogen atom or to convert it to a removablegroup, such as a reactive esterified group or to convert it to an aminogroup according to the previously described procedure. Azacycloaliphaticstarting materials which contain a carbonyl or thiocarbonyl groupadjacent to the aza nitrogen atom may be obtained by appropriateintramolecular or intermolecular acylation reactions; in the compoundsso obtainable a carbonyl group may be converted to a thiocarbonyl group,for example, by treatment with phosphorous pentasulphide. Startingmaterials of the formula 13 may be obtained, for *example by treatmentof a compound of the formula verted into a suitable enol derivativeaccording to known methodsA compound of the formulaPyr--C(=X)-Alk'==C(R)-N=Z may be obtained, for example, by treatment ofa compound of the formula PyrC(=X)AlkC(=O)R with a compound of theformula H-N=Z, preferably in the presence of an acidic reagent, e.g.p-toluenesulphonic acid, with the formation of the desired enamine, orfrom a compound of the formula PyrC(=X)Alk-CEN by treatment with acompound of the formula HN==Z under reductive conditions, for example,while treating with hydrogen in the presence of Raney nickel.

The compounds of the present invention are useful as medicaments, forexample, in the form of pharmaceutical preparations which contain thesecompounds together with pharmaceutical organic or inorganic, solid orliquid carriers which are suitable forenteral, for example, oral, orparenteral administration. These preparations may in solid form, e.g. astablets, drages, capsules or suppositories, or in the liquid form e.g.as solutions, suspensions or emulsions. They may optionally containauxiliary substances, such as preservatives, stabilisers, wetting agentsor emulsifiers, solubilizers, salts for regulating the osmotic pressure,buffers, dyestuffs or fiavouring substances. They may also contain othertherapeutically valuable substances and are formulated by methods whichare in themselves known.

The invention is described in more detail in the following examples. Thetemperatures are given in degrees centigrade.

EXAMPLE 1 A mixture of 4 g. of 4-acetyl-5-methyl-l-phenylpyrazole and3.2 g. of paraformaldehyde in 65 ml. of ethanol is treated with 4.25 g.of 4-cyano-4-phenyl-piperidine hydrochloride and 4 drops of concentratedhydrochloric acid, and boiled under reflux for 24 hours. On cooling oneobtains the crystalline 4-[3-(4-cyano-4-phenyl-piperidino)-1-oxo-propyl]-5-methyl-1-phenyl pyrazole hydrochloride of formula which melts at 214(with decomposition) after recrystallisation from isopropanol. The free4[3-(4-cyano-4-phenyl-piperidino)-1-oxo-propyl]-5-methyl1-phenylpyrazole is obtained by treatment with 1 N aqueous caustic soda.

EXAMPLE 2 A mixture of 5.6 g. of 4-acetyl-1-(4-bromophenyl)-S-methyl-pyrazole and 3.2 g. of paraformaldehyde in 75 ml. of ethanol istreated with 5.1 g. of 4-phenyl-4-npropyloxy-piperidine hydrochlorideand 4 drops of concentrated hydrochloric acid and boiled under refluxfor 24 hours. On cooling, 1-(4-bromophenyl)-5-methyl-4-[1- 14 oxo '3-(4-phenyl-4-n-propyloxy-piperidino) -propy1] -pyrazole hydrochloride offormula crystallises out. This melts at 240 (with decomposition) afterrecrystallisation from methanol. its free base may for example beobtained by treatment with 1 N aqueous caustic soda.

1 (4 fiuorophenyl) 5 methyl-4-[1-oxo-3-(4-phenyl-4-n-propyloxy-piperidino)-propyl]-pyrazole is prepared in a similarmanner; its monohydrochloride melts at 230 (with decomposition) afterrecrystallisation from a mixture of isopropanol and ether.

EXAMPLE 3 of formula I Br is obtained in crystalline form; afterrecrystallisation from methanol it melts at 180 (with decomposition).The free base is obtained by treatment with a suitable alkaline reagent,for example 1 N aqueous sodium hydroxide.

EXAMPLE 4 A mixture of 4.36 g. of 4-acetyl-l-(4-fluorophenyl)-5-methyl-pyrazole and 3.2 g. of paraformaldehyde in 70 ml. of ethanol istreated with 3.92 g. of 4phenyl-1,2,5,6-tetrahydropyridine hydrochlorideand 4 drops of concentrated hydrochloric acid and boiled under refluxfor 24 hours. On cooling, the crystallinel-(4-fluorophenyl)-5-methyl-4-[loxo 3 (4 phenyl 1,2,5,6 tetrahydro 1pyridyl)- propyl] -pyrazole hydrochloride of formula is obtained andmelts, after recrystallisation from isopropanol, at 192 (withdecomposition). The free compound is obtained by treating thehydrochloride with a suitable 15 alkaline reagent, for example 1 Naqueous sodium hydroxide.

EXAMPLE A mixture of 4 g. of 4-acetyl-l-phenyl-5-methyl-pyrazole and 3.2g. of ,paraformaldehyde in 60 ml. of ethanol is treated with 3.92 g. of4-phenyl-1,2,5,6-tetrahydro-pyridine hydrochloride and 4 drops ofconcentrated sulphuric acid and boiled under reflux for 24 hours. TheS-methyl- 4 [1 oxo-3-(4-phenyl-1,2,5,6-tetrahydro-l-pyridyl)-propyl]-1-phenyl-pyrazole hydrochloride hemihydrate of forcrystallises oncooling; after recrystallisation from a mixture of methanol, ethylacetate and ether, it melts at 195 (with decomposition). The freecompound is obtained by treatment with a suitable alkaline reagent, suchas 1 N aqueous sodium hydroxide.

The following compounds may be obtained by the above method and bychoosing the appropriate starting materials:

1- (4 bromophenyl) 5 methyl 4 [1 oxo 3 (4- phenyl 1,2,5 ,6 tetrahydro lpyridyl)-propyl]-pyrazole, the monohydrochloride of which melts at 205(with decomposition) after recrystallisation from methanol; and

1 (4 methyl phenyl) 5 methyl 4 [1 oxo 3- (4 phenyl 1,2,5,6 tetrahydro 1pyridyl) propyl]- pyrazole, the monohydrochloride of which melts at 205with decomposition) after recrystallisation from a mixture of methanol,ethyl acetate and ether.

EXAMPLE 6 A mixture of 5.6 g. of 4-acetyl-1-(5-bromo-2-pyridyl)-S-methyl-pyrazole and 3.2 g. of paraformaldehyde in 70 ml. of ethanol istreated with 3.92 g. of 4-phenyl-1,2,5,6- tetrahydropyridinehydrochloride and 1.5 ml. of concentrated hydrochloric acid and boiledunder reflux for 24 hours. The 1- 5 -bromo-2-pyridyl -5 -methyl-4-1-oxo-3- (4 phenyl 1,2,5,6 tetrahydro 1 pyridyl) propyl]- pyrazoledihydrochloride of formula crystallises on cooling; it melts at 225(with decomposition) after recrystallisation from methanol. The salt isconverted to the free compound by treatment with a suitable base, forexample 1 N aqueous sodium hydroxide.

16 EXAMPLE 7 A mixture of 10 g. of 4-acetyl-l-phenyl-S-methyl-pyrazoleand 4.5 g. of paraformaldehyde in ml. of ethanol is treated with 11.2 g.of 4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridine hydrochloride and 10drops of concentrated hydrochloric acid and boiled under reflux for 24hours. On cooling, the crystalline 4-{3-[4-(4-chlorophenyl) 1,2,5,6tetrahydro 1 pyridyl] 1 oxo-propyl} 5- methyl-l-phenyl-pyrazolehydrochloride of formula is obtained, which melts at 215 (withdecomposition) after recrystallisation from methanol. The free base isobtained by treating the hydrochloride with a base, for example, 1 Naqueous sodium hydroxide.

The 1-(4-bromophenyl) 4 {3-[4-(4-chlorophenyl)-1,2,5,6-tetrahydro-l-pyridyl] 1 oxo propyl}-5-methyl-' pyrazole isobtained in a similar way; its hydrochloride melts at 213-215 (withdecomposition) after recrystallisation from methanol.

EXAMPLE 8 A mixture of 56 g. of 4-acetyl-1-(4-bromophenyl)-5-methyl-pyrazole and 18 g. of paraformaldehyde in 500 ml. of absoluteethanol is treated with 24.4 g. of piperidine hydrochloride and 2 ml. ofconcentrated hydrochloric acid and boiled under reflux for 24 hours. The1-(4-bromo phenyl)-5-methyl-4-(l-oxo 3 piperidino-propyl)-pyrazolehydrochloride of formula crystallises on cooling and, afterrecrystallisation from a mixture of methanol and ether,melts at 205-207(with decomposition). The free base is obtained by treatment of the saltwith a suitable alkaline reagent, for example, 1 N aqueous sodiumhydroxide.

EXAMPLE 9 A mixture of 9.8 g. of 4-acetyl-l-carbethoxy-S-methylpyrazoleand 4.5 g. of paraformaldehyde in 125 ml. of ethanol is treated with 9.5g. of 4-phenyl-1,2,5,6-tetrahydropyridine hydrochloride and 10 drops ofconcentrated hydrochloric acid and boiled under reflux for 24 hours. Oncooling, one obtains the crystalline l-carbethoxy-S- methyl[1-oxo-3-(4phenyl-1,2,5,6-tetrahydro-1-pyridyl)- propyl]-pyrazolehydrochloride of formula which melts at 205 (with decomposition) afterrecrystallisation from methanol. It is converted to the free compound bytreatment with an alkaline reagent, for example, 1 N aqueou sodiumhydroxide.

f ln'oo-h-ongcmni which after recrystallisation from a mixture ofmethanol and isopropanol melts at 2l2-213 (with decomposition). The freebase is obtained by treating the hydrochloride salt with a suitablealkaline reagent, for example 1 N aqueous sodium hydroxide.

The following compounds are obtained in a similar manner, choosingappropriate starting substances: l-(4- bromophenyl)-4-{3-[4-(4chlorophenyl)-piperidino]-1- oxo-propy1}-5-methyl-pyrazole, themonohydrochloride of which melts at 225-227 (with decomposition) afterrecrystallisation from a mixture of methanol and isopropanol; and.4-[3-(4-phenyl-piperidino)-l-oxo-propyl]- S-methyl-l-phenyl-pyrazole,the monohydrochloride of Which'melts at 196 (with decomposition) afterrecrystallisation from a mixture of methanol and isopropanol.

' 1 EXAMPLE 12 A'mixture of 5.12 g. piperidyl) methyl pyrazolemonohydrochloride and 1.8 g. of paraformaldehyde in 60ml. of ethanol istreated with 3.92 g. of 4 phenyl 1,2,5,6 tetrahydropyridinehydrochloride and 4 drops of concentrated hydrochloric acid and boiledunder reflux for 24 hours. On cooling, one obtains the crystalline1-(1-methyl-4- piperidyl) 5 methyl -'4 1 [1-oxo-3-(4-phenyl-1,2,5,6-

tetrahydro 1 pyridyl) propyl] pyrazole dihydrochloride of formula which,after recrystallisation from a mixture of methanol and isopropanol,melts at 275 (with decomposition). The free compound is obtained bytreating the salt with a suitable base, for example, 2 N aqueous sodiumhydroxide solution.

The starting material used in the above reaction is obtained as follows:

A solution of 16.2 g. of ethoxymethylene-acetyl-acetone in 50 ml. ofdioxane is cooled to 0 and treated dropwise with a solution of 13.2 g.of l-methyl 4 hydrazinepiperidine in ml. of dioxane. The addition of thereagent is complete after 25 minutes, and the reaction mixture isstirred for 18 hours at room temperature. The solvent is evaporated andthe residue dissolved in benzene and filtered through an aluminium oxidecolumn. On evaporation, a colourless liquid is obtained and this isdissolved in ether and treated with a solution of hydrogen chloride gasin isopropanol; one thus obtains 4-acetyl-5- methyl 1 (1 methyl 4piperidyl) pyrazole monohydrochloride which, after recrystallisationfrom a mixture of methanol and isopropanol, melts at 302 (withdecomposition) EXAMPLE 13 crystallises out; after recrystallisation froma mixture of methanol and isopropanol, the product melts at 269-270(with decomposition) and is converted to the free compound by treatmentwith a suitable base, for example, 1 N aqueous potassium hydroxide.

EXAMPLE 14 A mixture of 2.94 g. of 4 acetyl 1 carbethoxy 5-methyl-pyrazole and 1.35 g. of paraformaldehyde in 60 ml. of ethanol istreated with 3.48 g. of 4 (4 chlorophenyl) piperidine hydrochloride and4 drops of concentrated hydrochloric acid; the mixture is boiled underreflux for 24 hours and then cooled. The l-car-bethoxy- 19 4 {3 [4 (4chlorophenyl) piperidino] 1 oxopropyl} 5 methyl-pyrazole hydrochlorideof formula ll 1 /o- .HCl 410 O C 11 crystallises out and melts at 2152l6(with decomposition) after recrystallisation from methanol. It isconverted to the free compound by treatment with a suitable alkalinereagent.

The starting material used in the above example is prepared as follows:

A mixture of 210 g. of ethoxymethylene-acetyl-acetone in 250 ml. ofether is cooled to and treated dropwise with a solution of 80 g. ofl-carbethoxy-hydrazine in 750 ml. of ether; the addition of the solutionis complete after 2 hours and the reaction mixture is stirred for 8hours at room temperature. The crystalline material is filtered oil andrecrystallised from a mixture of methanol and isopropanol; the resultinghydrazone melts at 140. 145 g. of the product are heated for 3 hours at160 in an atmosphere of nitrogen. After cooling to room temperature, theproduct is diluted with 500 ml. of ether and the mixture is evaporatedto dryness. The residue is recrystallised from ether and yields 4-acetyl1 carbethoxy 5 methyl pyrazole, which melts at 67. Its thiosemicarbazonemelts at 212 and its guanylhydrazone hydrochloride at 206.

EXAMPLE A solution of 2 g. of 5-methyl-4-{3-[4-(4-chlorophenyl) 1,2,5,6tetrahydro l pyridyl]-1-oxo-propyl}- 1 phenyl-pyrazole hydrochloride in100 ml. of 50% aqueous methanol is added dropwise at room temperature toa solution of 0.2 g. of sodium borohydride in 50 ml. of 50% aqueousmethanol. The reaction mixture is stirred for 1 hour at room temperatureand boiled under reflux for 5 hours. On cooling, one obtains acrystalline precipitate which is filtered oil. and yields the 4-{3-[4-(4 chlorophenyl) 1,2,5,6 tetrahydro 1 pyridyl]- l-hydroxy-propyl} 5methyl 1 phenyl pyrazole of formula which, after recrystallisation froma mixture of methylene chloride and n-hexane, melts at 135-136".

EXAMPLE 16 20 g. of 1-carbethoxy-5-methyl-4-[1-oxo-3-(4-phenyl- 1,2,5,6tetrahydro l pyridyl) propyl] pyrazole hydrochloride and 130 g. of cornstarch are intimately mixed and treated with a paste made of g. of maizestarch and 100 g. of distilled water. The mass is thoroughly kneaded,granulated and dried at 45. A mixture of 14 g. of talc and 6 g. ofmagnesium stearate is added to the granules and the mixture isthoroughly mixed and then converted to tablets, each containing 0.01 g.or 0.05 g. of the active substance.

EXAMPLE 17 A mixture of 1.6 g. of 4 acetyl 1 (4carbethoxyphenyl)-5-methyl-pyrazole and 0.54 g. of paraformaldehyde in20 ml. ethanol is treated with 1.3 g. of4-phenyll,2,5,6-tetrahydropyridine hydrochloride and 2 drops of 20concentrated hydrochloric acid. The reaction mixture is boiled underreflux for 24 hours. On cooling, the 1-(4- carbethoxy phenyl) 5 methyl 4[1 oxo 3 (4- phenyl 1,2,5,6 tetrahydro 1 pyridyl) propyl]- pyrazolehydrochloride of the formula crystallizes; it melts at 2l7-218 (withdecomposition) after recrystallisation from a mixture of methanol andisopropanol. The free base is obtained by basification of the aqueoussolution of the above salt with a solution of 1 N aqueous sodiumhydroxide.

The starting material used in the above reaction is prepared as follows:

A solution of 15.6 g. of ethoxy-methylene-acetyl-acetone in 50 ml. ofether is cooled to 0 and treated dropwise with 18 g. of4-hydrazine-benzoic acid ethyl ester in 200 ml. of ether. The additionof the latter is complete in 55 minutes and the mixture is stirred for18 hours at room temperature. The solvent is evaporated ofi to alford acrystalline residue. This is recrystallised from a mixture of ether andhexane to yield 1-(4-carbethoxyphenyl)-4-acetyl-5-methyl-pyrazole, M.P.114.

EXAMPLE 18 A mixture of 4.9 g. of4-acetyl-l-(3-chloro-4-methylphenyl)-5-methyl-pyrazole and 1.8 g. ofparaformaldehyde in 50 ml. of ethanol is treated with 4.5 g. of 4-phenyl l,2,5,6 tetrahydro pyridine hydrochloride and 4 drops ofconcentrated hydrochloric acid,; the reaction mixture is boiled underreflux for 24 hours. On cooling, the l (3 chloro 4 methyl phenyl) 5methyl- 4 [1 0x0 3 (4 phenyl 1,2,5,6 tetrahydrolpyridyl)-propyl]-pyrazole hydrochloride of the formula crystallises; itmelts at 225 (with decomposition) after recrystallisation from methanol.The free base is obtained by basification of the aqueous solution of thesalt with 1 N aqueous sodium hydroxide The starting material used isprepared as follows:

A solution of 44 g. of ethoxymethylene-acetyl-acetone in ml. of ether istreated dropwise at 0 with a solution of 44 g. of3-chloro-4-methyl-phenyl-hydrazine in 400 ml. ether. The addition of thelatter is complete in 2 hours and the reaction is stirred for 18 hoursat room temperature. The solvent is evaporated off, and the crystallineresidue is recrystallised from isopropanol to afford the 1 (3 chloro 4methyl phenyl) 4 acetyl 5- methyl-pyrazole, M.P. 84"; itsguanyl-hydrazone hydrochloride melts at 252.

EXAMPLE 19 A mixture of 10 g. of 4-acetyl-5-methyl-l-phenyl-pyrazole and4.5 g. of paraformaldehyde in ml. of ethanol is treated with 8.1 g. of3-aza-bicyclo[3,2,2]nonane hydrochloride and 17 drops of concentratedhydrochloric acid; the reaction mixture isboiled under reflux for 24hours. On cooling, the 4-[3-(3-aza-3-bicyclo[3,2,2] nonyl) 1 oxo propyl]methyl 1 phenylpyrazole-hydrochloride of the formula p crystallises; itmelts at 204 after recrystallization from a mixture of methanol andisopropanol. The free base is prepared by basification of the aqueoussolution of the above salt with a 1 N aqueous sodium hydroxide solution.1

Using the method outlined in the above example, the following compoundshave been prepared by choosing appropriate starting materials:

4 [3 (3 aza 3 bicyclo[3,2,2]nonyl)-1-oxo-propyl]- 1(2-hydroxyethyl)-5-methyl-py-razole, the monohydrochloride of whichmelts at 234 after recrystallization from methanol;

4 [3 (3 aza 3 bicyclo[3,2,2]nonyl)-1-oxo-propyl]- 1,-(4-bromophenyl)-5-methyl-pyrazole, the monohydrochloride of which meltsat 194-195" after recrystallization from a mixture of methanol andisopropanol;

4 7 [3 (3 aza 3 bicyclo[3,2,2]nonyl)-1-oxo-propyl]- 1 (ethoxy-carbonyl)5 methyl-pyrazole, the monohydrochloride of which melts at 203-204 afterrecrystallization from methanol; and

4 [3 (3 aza 3 bicyclo[3,2,2]nonyl)-1-oxo-propyl]- 5 methyl 1(4-methylphenyl)-pyrazole, the monohydrochloride of which melts at 210after recrystallization from a mixture of isopropanol and ether.

EXAMPLE 2o A mixture of 8.4 g. of 4-acetyl-1-(2-hydroxy-ethyl)-5-methyl-pyrazole and 4.5 g. of paraformaldehyde in 100 ml. of ethanol istreated with 6.7 g. of hexahydroazepine hydrochloride and drops ofconcentrated hydrochloric acid; the reaction mixture is boiled underreflux for 24 hours. On cooling and addition of ether, the4-[3-(1-hexahydroaze'pinyl) 1 7 oxo propyl]-1-(2-hydroxyethyl)-5-methyhpyrazole monohydrochloride of the formula crystallizes; it meltsat 156 (with decomposition) after recrystallization from methanol. Thefree base is obtained by basification of the aqueous solution of theabove salt with a solution of 1 N aqueous hydroxide.

A mixture of 6 g. of 4-acetyl-5-methyl-l-phenylpyrazole and 2.7 g. ofparaformaldehyde in 80 ml. of ethanol is treated with 6.2 g. ofhcxahydroazepine hydrochloride and 10 drops of concentrated hydrochloricacid. The reaction mixture is boiled under reflux for 24 hours; oncooling and diluting with ether, the 4-[3-(1-hexahydro 22 azepinyl) -'loxo pro-pyl]-5-methyl l-phenyI-pyrazole monohydrochloride of the formulais obtained, which melts at 175 after recrystallization from a mixtureof ethanol and ether.

Using the method outlined in the above example, the following compoundshave been prepared by choosing appropriate starting materials:

EXAMPLE 2 1 A solution of 1.8 g. of 4-[3-(1-hexahydroazepinyl)-1- oxopropyl] 5 methyl 1 phenyl pyrazole monohydrochloride in m1. of ethanolis hydrogenated over 0.1 g. of Adams platinum oxide catalyst at apressure of about 3 atmospheres. After the theoretical uptake ofhydrogen, the hydrogenated solution is filtered, evaporated to drynessand the residue is recrystallized from a mixture of ethanol and ethylacetate to afford the 4-[3-(1-hexa-' hydro azepiny1)-l-hydroxy-propyl]-5methyl-l-phenylpyrazole monohydrochloride of the formula which melts at2l5216 (with decomposition). The free base is obtained by basificationof the aqueous solution of the above salt with a solution of 1 N aqueoussodium hydroxide.

EXAMPLE 22 A mixture of 6 g. of 1-phenyl-4-acetyl-S-methyl-pyrazole and2.70 g. of paraformaldehyde in 80 ml. of ethanol is treated with 8.1 g.of 4-carbethoxy-4-phenyl-piperidine hydrochloride and 10 drops ofconcentrated hydrochloric acid; the reaction mixture is boiled underreflux for 24 hours. On concentrating the reaction mixture to one-thirdof its volume and adding 60 m1. of ether followed by cooling the 4 [3 (4carbethoxyA-phenyl-piperdino)-1- 23 oxo propyl] methyl l phenyl pyrazolemonohydrochloride of the formula crystallizes; it melts at 135 (withdecomposition) after recrystallization from a mixture of methanol andethyl acetate. The free base is prepared by basification of the aqueoussolution of the salt with a solution of 1 N aqueous sodium hydroxide.

EXAMPLE 23 crystallizes; it melts at 270-272 after recrystallizationfrom a mixture of methanol and isopropanol. The free base is prepared bybasification of the aqueous solution of the salt with a solution of 1 Naqueous sodium hydroxide.

EXAMPLE 24 A mixture of 5.12 g. of 4-acetyl-5-methyl-l-(l-methyl-4-piperidyl)-pyrazole monohydrochloride and 1.8 g. of paraformaldehydein 60 ml. of ethanol is treated with 3.24 g. of3-azobicyclo[3,2,2]nonane hydrochloride and 6 drops of concentratedhydrochloric acid; the reaction mixture is boiled under reflux for 24hours. On cooling, the 4{3-(3-aza-3-bicyclo[3,2,2]nonyl)-1-oxo-propyl}-5- methyl-l-(l-methyl-4-piperidyl)-pyrazole dihydrochloride of the formulacrystallizes; it melts at 268270 after recrystallization from methanoland isopropanol. The free base is prepared by basification of theaqueous solution of the above salt with a 1 N aqueous sodium hydroidesolution.

24 EXAMPLE 25 hydrochloric acid; the reaction mixture is boiled underreflux for 24 hours. On cooling, the 1-(4-fluorophenyl)-4- [1 oxo 3(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)-propyl]-5-phenyl-pyrazolemonohydrochloride of the formula All N .HCI

crystallizes; it melts at 198200 after recrystallization from a mixtureof methanol, isopropanol and ether. The free base is prepared bybasification of the aqueous solution of the above salt with a 1 Naqueous sodium hydroxide solution.

The starting material used in the above reaction is prepared as follows:

A mixture of 81 g. of benzoyl-acetone, 162 g. of triethyl orthoformateand 324 g. of acetic anhydride is boiled under reflux for 2 hours. Thevolatile compounds e.g. ethyl acetate etc., are distilled off, and thefraction boiling at 174/5 mm., is collected to yield theethoxy-methylene-benzoylacetone, which solidifies on cooling and meltsat 78-80 after recrystallization from a mixture of ether and hexane.

A solution of 21.8 g. of ethoxymethylene-benzoylacetone in 250 ml. ofether is cooled to 0 and treated dropwise with 12.6 g. of4-fluorophenyl-hydrazine in 300 ml. of ether; the addition of the latteris complete in 2 hours, and the reaction mixture is stirred for 18 hoursat room temperature. The solvent is evaporated off to afford acrystalline residue, which is recrystallized from isopropa nol to removethe 4-benzoyl-1-(4-fluorophenyl)-5-methylpyrazole, M.. 146. The motherliquor is evaporated to dryness and a solution of the residue isfiltered through a aluminum oxide column to afford the4-acetyl-1-(4-fluorophenyl)-5-phenyl-pyrazole, which is recrystallizedfrom aomixture of methylene chloride and hexane and melts at 8 -82.

EXAMPLE 26 crystallizes; it melts at l99200 after recrystallization fromisopropanol. The free base is obtained on basification of an aqueoussolution of the above salt with 1N aqueous sodium hydroxide solution.

The starting material used in the above reaction is prepared as follows:

A solution of 19.2 g. of ethoxymethylene-benzoylacetone in 500 ml. ofether is cooled to and treated dropwise with a solution of 16.5 g. of4-bromophenyl-hydrazine in 200 ml. of tetrahydrofuran. The addition ofthe latter is complete in 2 hours and the reaction mixture is stirredfor 18 hours at room temperature. The solvent is evaporated to afford acrystalline residue, which is chromatographed on a column of aluminumoxide. The fraction eluted with a 1:2-mixture of benzene and hexane is1- (4-bromophenyl)-4-benzoyl methyl-pyrazole, M.P. 127-128, which isfollowed by elution with a lzl-mixture of benzene and chloroform toyield 4-acetyl-l-(4- bromo-phenyl) 5-phenyl-pyrazole, which crystallizesfrom a mixture of isopropanol and hexane and melts at 143- 145".

EXAMPLE 27 -A mixture of 7.38 g. of4-acetyl-1-(4-methylmercaptophenyl)-5-methy1-pyrazole and 2.7 g. ofparaformaldehyde in 75 ml. of ethanol is treated with 5.88 of4-phenyl-l,2,5,6-tetrahydropyridine hydrochloride and drops ofconcentrated hydrochloric acid and boiled under reflux for 16 hours. The1-(4-methylmercapto-phenyl)-5- methyl-4-[l-oxo-3-(4-phenyl 1,2,5,6tetrahydro-l-pyridyl)-propyl]-pyrazole monohydrochloride of the formulaSICH3 I crystallizes on cooling; after recrystallization from methanol,it melts at 208-210". The free base is obtained by treatment withsuitable alkaline agent, such as a l N aqueous sodium hydroxidesolution.

The starting material used in the above example is prepared as follows:

88 g. of ethoxymethylene-acetylacetone in 300 ml. of ether is cooled to0 and a solution of 87 g. of 4-methylmercapto-phenyl-hydrazine in 700ml. of ether is added dropwise at 10. The reaction mixture is stirred atroom temperature for 10 hours, and the resulting crystalline precipitateis filtered 01f and recrystallized from a mixture of ether and petroleumether, to yield the l-(4-methylmercapto phenyl)-4-acetyl 5methyl-pyrazole, M.P. 112.

EXAMPLE 28 A mixture of 3.92 g. of4-acetyl-l-carboethoxy-S-methyl-pyrazole and 1.8 g. of paraformaldehydein 55 ml. of ethanol is treated with 5.4 g. of4-carboethoxy-4-phenylpiperidine hydrochloride'and 6 drops ofconcentrated hydrochloric acid; the reaction mixture is boiled underreflux for 24 hours. On concentrating the reaction mixture to one-thirdof its volume and adding 60 ml. of ether, followed by cooling at 0 for24 hours, the l-carboethoxy- 4-[3-(4-carboethoxy-4-phenyl 1piperidino)-1-oxo-propyl]-5-methyl-pyrazo1e monohydrochloride of theformula crystallizes; it melts at -167 after recrystallization from amixture of isopropanol, ethyl acetate and ether. The free base ispreparedby basification of an aqueous solution of the salt with a 1 Naqueous solution of sodium hydroxide. I

The following compounds may be obtained by the above method by choosingthe appropriate starting materials:

4- 3-(4-carboethoxy-4-phenyl piperidino)-1-0xo-propyl1-1-(4-fiuorophenyl)-5-methyl-pyrazole, the monohydrochloride of whichmelts at 140-142". after recrystallization from a mixture of ethylacetate and ether;

4-{ 3 [4-hydroxy-4- 3-trifluoromethylphenyl piperidino]1-oxo-propyl}-5methyl-l-phenyl-pyrazole, the monohydrochloride of whichmelts at 235-237 after recrystallization from isopropanol;

4- 3- (4-carboxamido-4-phenyl-piperidino) 1-oxo-propyl1- S-methyl 1phenyl-pyrazole, the monohydrochloride monohydrate of which melts at 223after recrystallization from a mixture of methanol and isopropanol;

4-[3-(4-carbomethoxy 4phenyl-piperidino)-l-oxo-propyl]-l-(4-fiuorophenyl)-5-methyl-pyrazole,the monohydrochloride of which melts at 199 after recrystallization froma mixture of methanol, isopropanol and ether;

4-[3-(4-carbo-n-butoxy 4phenylpiperidino)-1-oxo-propyl]-1(4-fluor0phenyl)-5-methyl-pyrazole, themonohydrochloride of which melts at 220-221 (with decomposition) afterrecrystallization from a mixture of ethyl acetate and ether;

4-[3-(4-carboethoxy-4-phenyl piperidino)-1-oxo-propyl1-l-(2-fluorophenyl)-5-methyl-pyrazole, the monohydrochloride monohydrateof which melts at 118120 after recrystallization from a mixture ofisopropanol, ethyl acetate and ether; and

1-(4-fiuorophenyD-4-[3-(4-methoxy 4 phenyl-l-piperidino) 1oxo-propyl]-5-methyl-pyrazole, the maleate monohydrate of which melts at115-116 after recrystallization from a mixture of isopropanol, ethylacetate and ether.

EXAMPLE 29 A mixture of 5.8 g. of 4-acetyl-l-(7-chloro-4-quinolinyl)-S-methyl-pyrazole and 1.8 g. of paraformaldehyde in 60 ml. of ethanol istreated with 4 g. of 4-phenyl-1,2,5,6- tetrahydro-pyridine hydrochlorideand 6 drops of concentrated hydrochloric acid and boiled under refluxovernight. The 1-(7-chloro-4-quinolinyl)-5-methy1-4-[1-oxo-3- (4phenyl-l,2,5,6-tetrahydro-l-pyridyl)-propyl] -pyrazole monohydrochlorideof the formula or \N/ crystallizes out on cooling; afterrecrystallization from a mixture of isopropanol and ether, it melts at153. The free base is obtained by treatment with suitable alkalineagent, such as a 1 N aqueous sodium hydroxide solution.

The starting material used in the above example is prepared as follows:

A mixture of 20.1 g. of ethoxymethylene-acetyl-acetone in 40 ml. oftetrahydrofuran is cooled to 0 and treated dropwise with a solution of25 g. of 7-chloro-4-hydrazino-quinoline in 250 ml. of tetrahydrofuran;the addition of the soltuion is complete after 2 hours, and the reactionmixture is stirred for 8 hours at room temperature. The crystallinematerial is filtered off and recrystallized from a mixture of methanoland isopropanol; the resulting hydrazone melts at -l90. 36 g. of thisproduct are heated for 6 hours at 190 in an atmosphere of nitrogen.After cooling to room temperature, the product is diluted with 50 ml. ofmethanol and the mixture is filtered. The residue is recrystallized frommethanol and affords 4- acetyl1-,(7-chloro-4-quino1inyl)-5-methyl-pyrazole, M.P. 142146.

The following compound is obtained by the method described in the aboveexample by choosing the appropriate starting material:

5 methyl 4 [1-oxo-3-(4-phenyl-l,2,5,6-tetrahydro-1- pyridyl) propyl] 1(4-quinolinyl)-pyrazole, the monohydrochloride of which melts at ZOO-202(with decomposition) after recrystallization from a mixture of methanol,isopropanol and ether.

EXAMPLE 30 A mixture of 7.38 g. of4-acetyl-1-(3-methyl-mercaptophenyl)-S-methyl-pyrazole and 2.7 g. ofparaformaldehyde in 75 ml. of ethanol is treated with 5.88 g. of 4-phenyl-1,2,5,G-tetrahydro-pyridine hydrochloride and 10 drops ofconcentrated hydrochloric acid and boiled under reflux for 16 hours. The1-(3-methylmercapto-phenyl)-5- methyl 4 [1 oxo3-(4-phenyl-l,2,5,6-tetrahydro-lpyridyl) propyl] pyrazolemonohydrochloride of the formula SCH crystallizes on cooling; afterrecrystallization from methanol, it melts at 183-184 ,(withdecomposition). The free base is obtained by treatment with suitablealkaline agent, such as a 1 N aqueous sodium hydroxide solution.

The starting material used in the above example is prepared as follows:

27.3 g. of ethoxymethylene-acetylacetone in 100 ml. of ether is cooledto and a solution of 27 g. of 3- methyl-mercapto-phenyl-hydrazine in 250ml. of ether is added dropwise at 10; the reaction mixture is stirred atroom temperature for 18 hours. The resulting crystalline precipitate isfiltered olf and recrystallized from a mixture of ether and petroleumether; the resulting 4-acetyll-(3-methylmercapto-phenyl)-5-methyl-pyrazole melts at 83.

The following compounds may be obtained by the procedure described inthe above example by choosing the appropriate starting materials:

5 methyl 1 (4 methylphenyl)-4-{3-[4-(4-methylphenyl)1,2,5,6-tetrahydro-l-pyridyl]-l-oxo-propyl}- pyrazole, themonohydrochloride of which melts at 201-202 after recrystallization froma mixture of methanol, isopropanol and ether; and

1 (4 bromophenyl) 5 methyl 4-{3-[4-(4-methylphenyl)1,2,5,6-tetrahydro-l-pyridyl]-1-oxo-propyl}- pyrazole, themonohydrochloride monohydrate of which melts at 207-208 afterrecrystallization from a mixture of methanol and isopropanol.

EXAMPLE 31 A mixture of 4.36 g. of 4-acetyl-1-(4-fiuorophenyl)-5-methyl-pyrazole and 1.8 g. of paraformaldehyde in 50 ml. of absoluteethanol is treated with 4.28 g. of4-(4-fluorophenyl)-1,2,5,6-tetrahydropyridine hydrochloride and 6 dropsof concentrated hydrochloric acid and boiled under reflux for 16 hours.The 1-(4-fluorophenyl)-4-{3-[4-(4- fluoophenyl)-1,2,5,6-tetrahydro-l-pyridyl]-1-oxo-propyl}- 5-methyl-pyrazolemonohydrochloride of the formula crystallizes on cooling; afterrecrystallization from a mixtures of chloroform and methanol, it meltsat 206-208. The free base obtained by treatment with suitable alkalineagent, such as a 1 N aqueous sodium hydroxide solution. The followingcompounds may be obtained by the above method by choosing theappropriate starting materials:

1 (4 bromophenyl) 4 {4 [4-(4-fluorophenyl)-l,2,5,6- tetrahydro 1pyridyl] l-oxo-propyl}-5-methyl-pyrazole, the monohydrochloride of whichmelts at 203- 204 (with decomposition) after recrystallization fromisopropanol, and

4-{3-[4-(4-fiuorophenyl) 1,2,5,6 tetrahydro 1pyrdyl]-1-oxo-propyl}-5-methyl 1 phenyl-pyrazole, the monohydrochlorideof which melts at 212 after recrystallization from a mixture ofmethanol, isopropanol and ether.

EXAMPLE 32 which melts at 220221. The free base is obtained by treatmentwith a suitable alkaline agent, such as a 1 N aqueous sodium hydroxidesolution.

The above compound is also prepared by Mannich condensation of 4-acetyll (4-fluorophenyl)-5-methylpyrazole with 4-(4-fluorophenyl)-piperidinehydrochloride in the presence of paraformaldehyde and catalytic amountsof concentrated hydrochloric acid in ethanolic solution according to theprocedure described in Example 1.

EXAMPLE 3 3 A mixture of 6.3 g. of4-acetyl-(3,5-bis-carbomethoxyphenyl)-5-methyl-pyrazole and 1.8 g. ofparaformaldehyde in ml. of ethanol is treated with 3.9 g. of4-phenyl-l,2,5,6-tetrahydropyridine hydrochloride and 5 drops ofconcentrated hydrochloric acid and boiled under reflux for 16 hours. Thel-(3,S-bis-carbomethoxyphenyl)- S-methyl-[l-oxo 3 (4-phenyl 1,2,3,5,6tetrahydro-l- 2'9 pyridyl) propyl]-pyrazole monohydrochloridemonohydrate of the formula I crystallizes; after recrystallization froma mixture of isopropanol and ether, it melts at 15 8-459". The free baseis obtained byitreatment of an aqueous solution of the above saltwithasuitable alkaline agent, such as a 1 N aqueous sodium hydroxidesolution.

-Thestarting material is prepared as follows:

A solution of 26.4 g. of ethoxymethylene-acetyl-acetone in 50 ml. ethylacetate is treated dropwise at with a solution of 37.5 g. of3,5-bis-carbomethoxy-phenyl-hydrazine in 200 mlfof dry ethyl acetate.The reaction mixture is stirred at room temperature for 48 hours and theresulting crystalline precipitate is filtered off and recrystallizedfrom isopropanol to alford the 4-acety1-(3,5-bis-carbomethoxyphenyl)-5methyl-pyrazole, which melts at 169.

EXAMPLE 34 -A mixture of 2.18 g. of 4-acetyl-1-(2-fluoropheny1)-S-rnethyl-pyrazole and 0.9 g. of paraformaldehyde in 30 ml. of absoluteethanol is treated with 2.2 g. of 4-(4- fluorophenyl) 1,2,5,6tetrahydropyridine hydrochloride and 3 drops of concentratedhydrochloric acid and boiled under reflux for 16 hours. The1-(2-fluorophenyl)-5-methyl-4-{3-[45(4-fluorophenyl) l,2,5,6tetrahydro-l-pyridyl] 1-oxo-propyl}-pyrazole monohydrochloride of theformula crystallizes on cooling; after recrystallization from a mixtureof methanol and isopropanol, it melts at 217-218". Therfreebase-is-obta-ined by treatment with suitable alkaline agent, such as a 1N aqueous sodium hydroxide solution.

crystallizes on .coolingrafter recrystallization from a mixture ofethanol, isopropanol and ether,it melts at 212.

The starting material for the above compound is prepared as follows:

A solution of 66 g. of ethoxymethyleneracetylacetone in 130 ml. of etheris treated dropwise at 0 with a solution of 102 g. of.3,Srbis-trifluoromethyl-phenykhydrazine in 600 ml. of ether. Thereaction mixture is stirred at;

room temperature for 18 hours and the resulting solution is evaporatedto dryness; the residue is recrystallized from isopropanol to aiford the4 acetyl-1-(3,5-bis-trifluoromethyl-phenyl) -5-methyl-pyrazole, M.P.112-1 13 EXAMPLE 36 A mixture of 6.54 g. of 4-acetyl-1-(4-fluorophenyl)-S-methyl-pyrazole and 2.7 g. of paraformaldehyde in ml. of ethanol istreated with 6.35 g. of 3-methyl-3- phenyl-piperidine hydrochloride 0nd10 drops of concentrated hydrochloric acid and boiled under reflux for16 hours. The 1 (4fluorophenyl)-5-methyl-4-[3,(3-methyl-3-phenyl-piperidino)-l-oxo-propyl]pyrazole monohydrochloride of the formula i 'HCl EXAMPLE 37 A mixture of2.8 g. of 4-acetyl-1-(2-hydroxyethyl)-5- methyl-pyrazole and 1.8 g. ofparaformaldehyde in 45 ml. of ethanol is treated with 4.4 g. of4-(4-fluorophenyl)- 1,2,5,6-tetrahydropyridine hydrochloride and 6 dropsby concentrated hydrochloric acid and boiled under reflux for 16 hours.The 4-{3-[4(4-fluorophenyl)-l,2,5,6-tetrahydro-I-pyridyl]-1-oxo-propyl}1 (2-hydroxyethyl)-5- methyl pyrazole monohydrochloride hemihydrate ofthe formula crystallizes on cooling. After recrystallization from amixture of isopropanol and ether, it melts at 108-110.

The following compounds may be obtained by the above method by choosingthe appropriate starting materials:

4-{3-[4-(4-chlorophenyl) 1,2,5,6-tetrahydro-l-pyridyl1- l-oxo-propyl}1-(Z-hydroxyethyl)-5-methyl-pyrazole, the monohydrochloride hemihydrateof which melts at 144-145 (with decomposition) after recrystallizationfrom a mixture of isopropanol and ether; and

l-(2-hydroxyethyl) 5 methyl-4-{3-[4-(4-methylphenyl) 1,2,5,6 tetrahydro1 pyridyl]-1-oxo-propyl}- pyrazole, the monohydrochloride hemihydrate ofwhich melts at 148 after recrystallisation from a mixture of isopropanoland ether.

31 EXAMPLE 38 A mixture of 11.81 g. of4-acetyl-1-[2-(4-bromophenylsulfonyloxy)-ethyl]-5-methyl-pyrazole and2.7 g. of paraformaldehyde in 1-05 ml. of ethanol is treated with 6.90g. of 4-(4-chlorophenyl)1,2,5,6-tetrahydropyridine hydrochloride and 9drops of concentrated hydrochloric acid and boiled under reflux for 16hours. The 1-[2-(4-bromophenyl-sulfonyloxy)-ethyl] 4{3-[4-(4-chlorophenyl)- l,2,5,6 tetrahydro 1pyridyl]-l-oxo-propyl}-5-methylpyrazole monohydrochloride of the formulacrystallizes out on cooling; after recrystallization from methanol, itmelts at 185-186. The free base is obtained by treatment of the aqueoussolution of the salt with a suitable alkaline agent, such as 1 N aqueoussodium hydroxide.

The starting material used in the above example is prepared as follows:

A solution of 83 g. of 4-acetyl-1-(2-hydroxyethyl)-5- methyl-pyrazole in750 ml. of dry tetrahydrofuran and 105 g. of triethylamine is treatedwith a solution of 128 g. of 4-bromobenzene sulfonyl chloride in 300 ml.of dry tetrahydrofuran. The reaction mixture is boiled under reflux for4 hours and cooled to room temperature. A crystalline precipitate formswhich is filtered off, the filtrate is evaporated to dryness, and theresidue is recrystallized from ethanol to yield the4-acetyl-1-[2-(4-brornophenyl-sulfonyloxy)-ethyl]-5-methyl-pyrazole,M.P. 142.

The following compounds may be obtained according to the above method bychoosing appropriate starting materials:

1-[2-(4-bromophenyl-sulfonyloxy)-ethyl] 5 methyl-4- [l-oxo-3-(4-phenyl1,2,5,6 -tetrahydro 1 pyridyl)- propyl] pyrazole, the monohydrochlorideof which melts at 251 after recrystallization from methanol; and

1-[2-(4-bromophenyl-sulfonyloxy)-ethyl] 5 methyl-4- {3(4-(4-methyl-phenyl) 1,2,5,6tetrahydro-l-pyridyl]l-oxo-propyl}-pyrazole, the monohydrochloride ofwhich melts at 238 after recrystallization from methanol.

iEXAMPL-E 39 A mixture of 2.9 g. of 4-acetyl-5-methyl-l-(3,4,5-trimethoxyphenyl)-pyrazole and 0.9 g. of paraformaldehyde in ml. of ethanolis treated wtih 1.9 g. of 4-phenyl- 1,2,5,6-tetrahydropyridinehydrochloride and 3 drops of concentrated hydrochloric acid and boiledunder reflux for 1-6 hours. The 5-methyl-4-[1-oxo-3-(4-p'henyl-1,2,5,'6-tetrahydro 1 pyridyl)-propyl] 1 -'(3,4,5-trimethoxyphenyl)-pyrazolemonohydrochloride of the formula crystallizes on cooling; afterrecrystallization from methanol, it melts at 255 (with decomposition).The free base is obtained by treatment of an aqueous solution of theabove salt with a suitable alkaline agent, such as 1 N aqueous sodiumhydroxide.

The starting material used in the above example, is prepared as follows:A solution of 7.4 g. of ethoxymethylene-acetylacetone in .100 ml. ofether is treated at 0 with portionwise addition of 7.4 g. of3,4,S-trimethoxy-phenyl-hydrazine in 700 ml. of ether. The reactionmixture is stirred at room temperature for 18 hours and then evaporatedto dryness. The residue is recrystallized from ethanol to afford the4-acetyl-5-methyl 1 (3,4,5-trimethoxyphenyl)pyrazole, M.P. 174.

EXAMPLE 40 A mixture of 6.8 g. of 4-acetyl-1-(3-hydroxyethyl)-5-methyl-pyrazole and 3.6 g. of paraformaldehyde in ml. of ethanol istreated wtih 7 g. of decahydroquinoline hydrochloride and 10 drops ofconcentrated hydrochloric acid and boiled under reflux for 24 hours. The4-[3- (decahydro-l-quinolinyl) 1 oxo-propyl] 1 (2-hydroxyethyl)-5-methyl-pyrazole monohydrochloride of the formula N C-CH;

crystallizes on cooling; after recrystallization from isopropanol, itmelts at 260.

EXAMPLE 41 crystallizes on cooling; after recrystallization from a mix--ture of isopropanol and ether, it melts at 225. The free base isobtained by treatment of the aqueous solution of the above salt with asuitable alkaline agent, such as a 1 N aqueous sodium hydroxidesolution.

The starting material used in the above example, is prepared as follows:

A solution of 234 g. of ethoxymethylene-acetylacetone in 300 ml. etheris cooled to 0 and a solution of 69 g. of methyl-hydrazine in 900 ml.ether is added dropwise over a period of 4 hours. The reaction mixtureis stirred at 10 for 18 hours and the crystalline precipitate isfiltered 01f. It is recrystallized from isopropanol to afford the4-acetyl- 1,5-dimethyl-pyrazole, M.P. 78-79".

The following compound may be prepared by the method described above 'bychoosing the appropriate starting materials:

4 {3-[4-(4-chlorophenyl)-1,2,5,6-tetrahydro-l-pyridyl]- 1oxo-propyl}-1,5-dimethyl-pyrazole, the monohydrochloride of which meltsat 204 (with decomposition) after recrystallization from isopropanol.

EXAMPLE 42 A mixture of 4 g. of 4-acetyl-1-{2-[4-(4-fluorophenyl)- 1piperazino]-ethyl}-5-methyl-pyrazole monohydrochloride dihydrate and 0.9g. of paraformaldehyde in 30 ml. of ethanol is treated with 2.3 g. of4-(4-chlorophenyl)- l,2,5,6 tetrahydro-pyridine hydrochloride and 4drops of concentrated hydrochloric acid and the reaction mixture boiledunder reflux for 24 hours. The 4-{3-[ (4-chlorophenyl) l,2,5,6tetrahydro-1-pyridyl]-l-oxo-propyl}-1- {2- [4(4-fluorophenyl)-1-piperazino]-ethyl}-5-methyl pyrazole dihydrochloridedihydrate of the formula crystallizes out on cooling. Afterrecrystallization from a mixture of isopropanol and ether, it melts at172 (with decomposition). The base is obtained by treatment of theaqueous solution of this salt with a suitable alkaline agent, such as a1 N aqueous sodium hydroxide solution.

The starting material used in the above example is prepared as follows:

A solution of 9.7 g. of4-acetyl-1-[2-(4-bromophenylsulfonyloxy)-ethyl]-5-methyl-pyrazole in 150ml. dioxane is treated with 12.5 g. of 4-(4-fluorophenyl)-piperazine andheated for 8 hours in a steel tube under pressure at 160. On cooling,the reaction mixture is taken up in 300 ml. of methanol and the solventis evaporated 01f to dryness. The residue is suspended in 200 ml. waterand extracted with ethyl acetate. The organic extract is dried overanhydrous sodium sulfate and evaporated to dryness. The residue isdissolved in ether and adjusted to pH 2 with a solution of hydrogenchloride gas in isopropanol. The crystalline precipitate is filtered offand recrystallized from isopropanol to afford the 4-acetyl-1-{2-[4-(4-fluorophenyl) 1 piperazino]-ethyl}-5-methyl-pyrazolemonohydrochloride dihydrate, M.P. 198 (with decomposition).

EXAMPLE 43 A solution of 195 g. of 4-{3-[4-(4-fluorophenyl)-1,2,5, 6tetrahydro-l-pyridyl]-1-oxo-propyl}-I-(Z-hydroxyethyl)-S-rnethyl-pyrazolein 1000 ml. of methylene chloride is treated with a hot solution of 105g. of citric acid in 200 ml. of methanol. The clear solution isconcentrated and diluted with ether to aiford a crystalline precipitatewhich is filtered olf and recrystallized from a mixture of methanol andether to yield the citrate of 4-{3-[4-(4-fiuorophenyl)-125,6 tetrahydrol-pyridyl]-1-oxo-propyl}-l-" (2-hydroxyethyl)-5-methyl-pyrazole, whichmelts at 136- 138".

EXAMPLE 45 A solution of 30 g. of 1-(2-hydroxyethyl) -5-methyl-4-1-oxo-3-(4-phenyl-1,2,5,6-tetrahydro-1-pyridyl)-propyl]- pyrazolemonohydrochloride in 800 ml. of water, containing 80 ml. methanol istreated with a saturated aqueous solution of sodium hydrogen carbonateto bring it to pH 7.5. The crystalline precipitate is filtered olf andtriturated with water, then recrystallised from a mixture of methylenechloride and hexane to aiford the 1-(2-hydroxyethyl)-S-methyl-4-[1-oxo-3-(4-phenyl 1,2,5,6 tetrahydro 1-pyridyl)-propyl]-pyrazole, which melts at -147".

EXAMPLE 46 A solution of 22.4 g. of 1-(2-hydroxyethyl)-5-methyl-4-[l-oxo-3-(4-phenyl-1,2,5,6 tetrahydro 1 pyridyl)- propyl]-pyrazole in250 ml. of warm methylene chloride is treated with warm solution of 9.8g. of maleic acid in 50 ml. of ethanol. The solution is concentrated tosmall volume and diluted with ether. The resulting crystallineprecipitate is filtered off and recrystallized from a mixture ofmethanol, isopropanol and ether to aiford the maleate of1-(Z-hydroxyethyl)-5-methyl-4-[1-oxo-3-(4-pheny1 1,2,5,6-tetrahydro-1-pyridyl)-propyl]-pyrazole, which melts at 112.

EXAMPLE 47 A mixture of 3.87 g. of4-acetyl-1-[3-(4-bromophenylsulfonyloxy)-ethyl]-5-methyl-pyrazole and0.9 g. of paraformaldehyde in 40 ml. of absolute ethanol is treated with2.14 g. of 4-(4-fluorophenyl)-l,2,5,6-tetrahydro-pyridine hydrochlorideand 3 drops of concentrated hydrochloric acid and boiled under refluxduring 16 hours. The 1-[2- (4- bromophenyl-sulfonyloxy)-ethyl]-4-{3 [4(4 fluorophenyl)-1,2,5,6-tetrahydro-l-pyridyl]-1-oxo propyl} 5-methyl-pyrazole monohydrochloride of the formula crystallizes out oncooling; after recrystallization from methanol, it melts at 206-207".The free base is obtained by treatment of an aqueous solution of thesalt with a saturated aqueous solution of sodium hydrogen carbonate.

EXAMPLE 48 A mixture of 2.52 g. of 4-acety-l-1-(2-hydroxy-ethyl)-S-methyl-pyrazole and 1.35 g. of paraformaldehyde in 40 ml. absoluteethanol is treated with 3.96 g. of4-(3-trifluoromethyl-phenyl)-1,2,5,6-tetrahydro pyridine hydrochlorideand 4 drops of concentrated hydrochloric acid and boiled under refluxfor 16 hours. The solution is concentrated to a volume of 10 ml. anddiluted with 20 ml. of isopropanol, then again concentrated to a volumeof 10 ml. 0n addition of 20 ml. of dry ether, followed by cooling to 0,the 1-(Z-hydroxyethyl)-5-methyl-4-{1-oxo-3-[4-(3-trifluoromethyl-phenyl)-1,2,5,6 tetrahydro 1 pyridyl]-propyl}-pyrazole monohydrochloride of the formula CHrCH- OH crystallizesout; after recrystallization from a mixture of methanol, isopropanol andether, it melts at 200. The free base is obtained by treatment of anaqueous solution of the salt with a saturated aqueous sodium hydrogencarbonate solution.

EXAMPLE 49 A mixture of 4.64 g. of4-acetyl-1-(3-fluoro-4-methylphenyl)-S-methyl-pyrazole and 1.8 g. ofparaformaldehyde in 50 ml. of absolute methanol is treated with 4.25 g.of 4-(4-fluorophenyl)-1,2,5,6-tetrahydro-pyridine hydrochloride and 5drops of concentrated hydrochloric acid and boiled under reflux for 24hours. The solution is concentrated to a volume of 10 ml., diluted with20 ml. of isopropanol, again concentrated to 10 ml. and diluted with 20ml. of dry ether. On cooling, the 1-(3-fluoro-4-methylphenyl) -4-{3-[4-(4 fluorophenyl)-1,2,5,6 tetrahydro 1- 35pyridyl]-1-oxo-propy1}-5-methy1 pyrazole monohydrochloride of theformula l CH crystallizes out; after recrystallization from a mixture ofmethanol, isopropanol and ether, it melts at 205-207". The free base isobtained by treatment of an aqueous solution of the salt with asaturated aqueous sodium hydrogen carbonate solution.

The starting material is prepared as follows:

A solution of 12.5 g. of 3-fiuoro-4-methyl-aniline in 62 ml. ofconcentrated hydrochloric acid is treated at with a solution of 7 g. ofsodium nitrite in 31.5 ml. of water. After the diazotisation iscomplete, the diazonium salt solution is treated dropwise at 0 over aperiod of 4 hours with a solution of 50 g. of stannous chloridedihydrate in 175 cc. of concentrated hydrochloric acid. The reactionmixture is stirred for an additional 2 hours, then the resultingcrystalline precipitate is filtered off, suspended in 100 ml. water andmade alkaline with a 25% aqueous solution of sodium hydroxide. Thealkaline solution is extracted with benzene, the organic solution isdried over anhydrous sodium sulphate and evaporated to dryness. Theresidue is dissolved in 50 ml. isopropanol and treated with a N solutionof dry hydrogen chloride gas in dry isopropanol. The crystallineprecipitate is filtered off and recrystallized from a mixture ofmethanol and ether to alford the 3-fluoro-4-methyl-phenyl-hydrazinehydrochloride, M.P. 265 (with decomposition). The free base is obtainedby treatment of the aqueous solution of the salt with a 2 N aqueoussodium hydroxide solution, followed by extraction with ether.

A solution of 7.4 g. of 3-fluoro-4-methyl-phenyl-hydrazine in 100 ml. ofdry ether is added dropwise at 0 to a solution of 8.3 g. ofethoxymethylene-acetylacetone in 50 ml. of dry ether. The reactionmixture is stirred at room temperature for 24 hours, the solvent is thenevaporated and the residue is triturated with hexane to yield the4-acetyl-1-(3-fluoro-4-methyl-phenyl) 5 methyl-pyrazole, M.P. 80 afterrecrystallization from hexane.

EXAMPLE 50 A mixture of 4.64 g. of4-acetyl-1-(4-fluoro-3-methylphenyl)-5-methyl-pyrazole and 1.8 g. ofparaformaldehyde in 50 ml. of absolute ethanol is treated with 4.28 g.of 4-(4-fluorophenyl)-1,2,5,6-tetrahydro-pyridine hydrochloride and 5drops of concentrated hydrochloric acid and boiled under reflux for 24hours. The solution is concentrated to a volume of 8 ml., diluted with25 ml. of isopropanol, again concentrated to 10 ml. and diluted with 20ml. of ether. On cooling, the 1-(4-fluoro-3-methy1-phenyl)-4-{3-[4-(4-fluorophenyl) 1,2,5,6tetrahydro-lpyridyl]-1-oxo-propyl} 5 methyl-pyrazole monohydrochlorideof the formula 36 crystallizes out; after recrystallization from amixture of ethanol and ether, it melts at 198. The free base is obtainedby treatment of an aqueous solution of the salt with a saturated aqueoussodium hydrogen carbonate solution.

The starting material is prepared as follows:

A solution of 18.1 g. of 4-fluoro-3-methyl-aniline in ml. concentratedhydrochloric acid is diazotised and the diazonium salt reduced in themanner described in Example 49. The resulting4-fluoro-3-methyl-phenyl-hydrazine hydrochloride is recrystallized froma mixture of ethanol and ether, which melts at 198200 (withdecomposition). The free base is obtained by treatment of the aqueoussolution of the salt with a 2 N aqueous sodium hydroxide solution,followed by extraction with ether.

A solution of 10.5 g. of 4-fluoro-3-methyl-phenyl-hydrazine in ml. ofdry ether is added dropwise at 0 to a solution of 11.7 g. ofethoxymethylene-acetylacetone in 50 ml. of dry ether. The reactionmixture is stirred at room temperature for 24 hours, the solvent is thenevaporated and the residue is triturated with benzene to afford 4acetyl-(4-fluoro-3-methyl-phenyl)-5-methyl-pyrazole, M.P. 146-147 afterrecrystallization from hexane.

EXAMPLE 51 A mixture of 6.8 g. of 4-acetyl-1-(2-hydroxyethyl)-5methyl-pyrazole and 3.6 g. of paraformaldehyde in 95 ml. of absoluteethanol is treated with 8.5 g. of 4-hydroxy- 4-phenyl-piperidinehydrochloride and 10 drops of concentrated hydrochloric acid and boiledunder reflux for 16 hours. The solution is concentrated to a volume of10 ml., diluted with 10 ml. of dry ether and cooled to 0 for 48 hours.The crystalline precipitate is recrystallized from a mixture ofisopropanol and ether to afford the 1-(2-hydroxyethyl) -4- [3-(4-hydroxy-4-phenyl-pip eridino -1-oxopropyl]-5-methyl-pyrazolemonohydrochloride of the formula which melts at 220-221. The free baseis obtained by treatment of an aqueous solution of the salt with asaturated aqueous sodium hydrogen carbonate solution.

EXAMPLE 52 A mixture of 2 g. of1-(2-hydroxyethyl)-4-[3-(4-hydroxy-4-phenyl-piperidino) 1oxo-propyl1-5-methylpyrazole monohydrochloride and 20 ml. ofconcentrated sulphuric acid is allowed to stand at room temperature forone hour. The mixture is poured into ice and made alkaline with asaturated aqueous solution of sodium hydrogen carbonate. The crystallineprecipitate is filtered off and recrystallized from a mixture ofmethylene chloride and hexane to afford the1-(2-hydroxyethyl)-5-methy1-4-[1-oxo-3-(4-phenyl-1,2,5,6-tetrahydro 1pyridy1)- propyl]-pyrazole, which melts at -147.

EXAMPLE 53 A solution of 6 g. of 1-(3-fluorophenyl)-4-{3-[4-(4-fluorophenyl) 1,2,5,6tetrahydro-l-pyridylJ-l-oxo-propyl}-5-methyl-pyrazole monohydrochloridein 200 ml. of 50% aqueous methanol is treated with a 10% aqueoussolution of sodium carbonate. The crystalline precipitate isrecrystallized from a mixture of methylene chloride and hexane to yieldthe 1-(3-fiuorophenyl)-4-{3-[4-(4- fluorophenyl)-1,2,5,6-tetrahydro 1pyridyl]-1-oxo-propyl}-5-methyl-pyrazole, which melts at 133-135.

37 EXAMPLE 54 which melts at 126-128.

EXAMPLE 55 Asolution of 13 g. of 1-(4-fluorophenyl)-4-{3-[4-(4-fiuorophenyl)-1,2,5,6-tetrahydro 1pyridyl]-1-oxo-propyl}--methyl-pyrazole monohydrochloride in 300 ml. of50% aqueous methanol is treated with a aqueous solution of sodiumhydroxide. On cooling, a crystalline precipitate is formed, which isfiltered off and recrystallized from a mixture of methylene chloride andhexane to afford the 1-(4 fluorophenyl)-4-{3-[4-(4-fluorophenyl)-1,2,5,6 tetrahydro 1 pyridyl]-1-oxo-propyl}-5-methylpyrazole, whichmelts at 150.

EXAMPLE 5 6 A solution of 11 g. of 1-(4-fluorophenyl)-4-{3-[4-(4-fluorophenyl)-1,2,5,6-tetrahydro 1pyridyl]-1-oxo-propyl}-5-methyl-pyrazole in 500 ml. of methanol istreated with 1.1 g. of sodium borohydride in 20 ml. of 50% aqueousmethanol; the reactioin mixture is boiled under reflux :for 5 hours. Oncooling, a crystalline precipitate is formed which is filtered off andrecrystallized from a mixture of methylene chloride and hexane to affordthe 1-(4-fiuorophenyl)- 4-{3-[4-(4-fluorophenyl) 1,2,5,6tetrahydro-lpyridyl]-1 hydroxyapropyl}-S-methyl-pyrazole of the formulawhich melts at 157-158.

" EXAMPLE s7 EXAMPLE 58 A mixture of 6.9 g. of4-acetyl-1,S-dimethyl-pyrazole and 4.5 g. of paraformaldehyde in ml. ofisopropanol is treated with 8.5 g. of 4,4-pentamethylenepiperidinehydrochloride and 1.5 ml. of concentrated hydrochloric acid; thereaction mixture is boiled under reflux for 24 hours. On cooling to roomtemperature, the 4[3-(3-aza-3-spiro [5 .5 ]undecyl)-1-oxo propyl]-1,5-dimethyl-pyrazole monohydrochloride of the formula II N -0H,

crystallizes out; it melts at 258 (with decomposition) afterrecrystallization from a mixture of methanol and ether. The free base isobtained by treatment of an aqueous solution of the above salt with a 1N aqueous sodium hydroxide solution.

EXAMPLE 59 A mixture of 8.1 g. of4-acetyl-l-[2-(4-fluorophenylsulfonyloxy)-ethyl]-5-methyl-pyrazole and2.25 g. of paraformaldehyde in 80 ml. of absolute ethanol is treatedwith 4.88 g. of 4-phenyl-1,2,5,6-tetrahydro-pyridine hydrochloride and0.8 ml. of concentrated hydrochloric acid and boiled under reflux for 16hours. The 1-[2-(4-fluorophenyl-sulfonyloxy)-ethyl] 5methyl-4-[3-(4-phenyl-l,2,5,6- tetrahydrol-pyridyl) -1-oxo-propyl]pyrazole monohydrochloride of the formula N n01 oH -oHr-o-s m-Q-T whichmelts at 183 after recrystallization from a mixture of methanol andisopropanol. The free base is prepared by the treatment of an aqueoussolution of the above salt with saturated aqueous solution of sodiumhydrogen carbonate.

The starting material is prepared as follows:

A solution of 21.84 g. of 4-acetyl-1-(2-hydroxyethyl)- S-methyl-pyrazolein 250 ml. of dry tetrahydrofuran and 15.15 g. of triethylamine istreated with a solution of 25.35 g. of 4-fiuorophenyl-sulfonylchloridein ml. of dry tetrahydrofuran; the reaction mixture is boiled underreflux for 4 hours and filtered hot. The filtrate is evaporated todryness and the residue is suspended in water and extracted with ethylacetate; the organic extract is dried over anhydrous sodium sulfate andevaporated to dryness. The residue is recrystallized from a mixture ofisopropanol and hexane to afford the 4-acetyl- 1[2-(4-fluoro-phenyl-sulfonyloxy)-ethyl]-5-methyl-pyrazole, M.P. 107-108.

EXAMPLE 60 A mixture of 8.1 g. of 4-acetyl-1-[2-(4-fiuorophenylsulfonyloxy)-ethyl]-5-methyl-pyrazole and 2.25 g. of paraformaldehyde in80 ml. of absolute ethanol is treated with 5.35 g. of 4 (4 fluorophenyl)l,2,5, 6-tetrahydropyridine hydrochloride and 0.8 ml. of concentratedhydrochloric acid and boiled under reflux for 16 hours. The resulting 1-[2-(4-fiuorophenyl-sulfony1oxy)-ethyl]-4-{3- [4(4-fiuorophenyl)-l,2,5,6-tetrahydro-l-pyridyl]-l-oxo- 39 propyl} methylpyrazole monohydrochloride of the formula melts at 165-167 afterrecrystallization from a mixture of ethanol and ether. The free base isobtained by treatment of an aqueous solution of the salt with asaturated aqueous solution of sodium hydrogen carbonate.

EXAMPLE 61 A solution of 3.33 g. of 4-{3-[4-(4-fluorophenyl)-1,2, 5,6tetrahydro l-pyridyl]-1-oxo-pr0pyl}-1-(2-hydroxyethyl)-5-methyl-pyrazolein 100 ml. tetrahydrofuran and 1.5 g. of triethylamine is treated with1.95 g. of 4-fluorophenyl-sulfonylchloride in 50 ml. of tetrahydrofuran;the reaction mixture is boiled under reflux for 4 hours and filteredhot. The filtrate is evaporated to dryness and the residue is treatedwith ethanolic hydrogen chloride. The resulting crystalline precipitateis recrystallized from a mixture of methanol and isopropanol to atfordthe 1-[2- (4 fluorophenyl sulfonyloxy)-ethyl]-4-{3-[4-(4-fluorophenyl)1,2,5,6 tetrahydro-l-pyridyl]-1-oxo-propyl}-5- methyl-pyrazolehydrochloride; the product is identical with the compound described inExample 60; it melts at 165-167 and the mixed melting point withcompound of Example 60 remains unchanged.

EXAMPLE 62 A solution of 6.86 g. of4-acetyl-1-[2-(4-chlorophenylsulfonyloxy)-ethyl1-5-methyl-pyrazole and1.8 g. of para formaldehyde in 60 ml. absolute ethanol is treated with4.28 g. of 4-(4-fluorophenyl)-1,2,5,6-tetrahydro-pyridine hydrochlorideand 0.66 ml. of concentrated hydrochloric acid and boiled under refluxfor 16 hours. The 1-[2-(4- chlorophenyl sulfonyloxy)-ethyl]-4-{3-[4-(4-fluorophenyl)1,2,5,6-tetrahydro-l-pyridyl]-1-0xo-propyl}-5-methyl-pyrazolemonohydrochloride of the formula which melts at 180182 afterrecrystallization from a mixture of methanol, isopropanol and ether. Thefree base is obtained by treatment of an aqueous solution of the saltwith a saturated aqueous sodium hydrogen carbonate solution.

The starting material is prepared as follows:

A solution of 21.84 g. of 4-acetyl-1-(2-hydr0xyethyl)- S-methyl-pyrazolein 250 ml. of tetrahydrofuran and 15.15 g. of triethylamine is treatedwith a solution of 27.43 g. of 4-chloro-phenyl-sulfonyl chloride in 150ml. of dry tetrahydrofuran. The reaction mixture is boiled under refluxfor 4 hours, filtered hot and evaporated to dryness. The residue issuspended in 100 ml. water and extracted with ethyl acetate. The organicextract is dried with anhydrous sodium sulfate and evaporated todryness. The residue is recrystallized from a mixture of methylenechloride and hexane to yield the 4-acetyl-1-[2-(4- chlorophenylsulfonyloxy) ethyl] 5 methyl-pyrazole, M.P. 125-126".

EXAMPLE 63 A mixture of 6.86 g. of4-acetyl-1-[2-(4-chlorophenylsulfonyloxy)-ethyl]-5-methyl-pyrazole and1.8 g. of paraformaldehyde in 60 ml. of absolute ethanol is treated with3.92 g. of 4-phenyl-1,2,5,6-tetrahydro-pyridine hydrochloride and 0.66ml. of concentrated hydrochloric 40 acid and boiled under reflux for 16hours. The 1-[2-(4- chlorophenyl 'sulfonyloxy) ethyl] 5 methyl-4[3-(4-phenyl 1,2,5,6-tetrahydro-l-pyridyl)-1-oxo-propyl]-pyrazolemonohydrochloride of the formula N hm-om-o-smQ-m melts at 200 afterrecrystallization from methanol. The

free base is obtained by treatment of an aqueous solution of the abovesalt with a saturated aqueous sodium hydrogen carbonate solution.

EXAMPLE 64 A mixture of 4.8 g. of4-acetyl-1-(Z-dimethylaminoethyl)-5-methyl-pyrazole and 2.25 g. ofparaformaldehyde in 50 ml. isopropanol is treated with 4.8 g. of 4-phenyl-1,2,5,6-tetrahydro-pyridine hydrochloride and 8 drops ofconcentrated hydrochloric acid; the reaction mixture is boiled underreflux for 16 hours. The solvent is distilled off, the residue istriturated with ethereal hydrogen chloride, and on cooling to 0 for 24hours, a crystalline precipitate is formed which is filtered off andrecrystallized from a mixture of isopropanol and ether to afford the 1(2 dimethylaminoethyl)-4-[l-oxo-3-(4-phenyl-l,2,5,6-tetrahydro-l-pyridyl)-propyl] 5 methylpyrazoledihydrochloride of the formula which melts as the monohydrate at 185-186. The free base is obtained by treatment of an aqueous solution ofthe above salt with a saturated aqueous solution of sodium hydrogencarbonate.

The starting material is prepared as follows:

A solution of 5.7 g. of ethoxymethylene-acetylacetone in 150 ml. etheris treated at 0 dropwise with 39 g. of 2-dimethylaminoethyl-hydrazine in350 ml. of ether. The reaction mixture is stirred at room temperaturefor 24 hours and then evaporated to dryness. The residual oil isredissolved in ether and treated with a saturated solution of maleicacid in isopropanol. A crystalline precipitate is formed which isfiltered and recrystallized from a mixture of isopropanol and ether toaflord the 4-acetyl-1- (Z-dimethylaminoethyl)-5-methyl-pyrazole maleate,M.P. 142.143. The free base is obtained from this salt by treatment ofthe latter with aqueous ammonium hydroxide.

EXAMPLE 65 A mixture of 7.8 g. of 4-acetyl-1-(2-diethylaminoethyl)-S-methyl-pyrazole hydrochloride and 2.7 g. of paraformaldehyde in ml. ofisopropanol is treated with 5.8 g. of4-phenyl-1,2,5,6-tetrahydro-pyridine hydrochloride and 10 drops ofconcentrated hydrochloric acid; the reaction mixture is boiled underreflux for 16 hours. On cooling and addition of ether, theI-(Z-diethylaminoethyl)-4-[1-oxo 3 (4-phenyl 1,2,5,6 tetrahydro-1-pyridyl)-propyl]-5-methyl-pyrazole dihydrochloride of the formula

